Aminotetraline derivatives

ABSTRACT

The present application relates generally to amino tetraline derivative compounds and methods of use, specifically, embodiments including compounds of formula (I) described herein, pharmaceutically acceptable salts and solvates. More specifically, this application relates to amino tetraline derivative compounds and uses of such compounds producing medicaments for the treatment of various disease and conditions including movement disorders and disorders of the central nervous system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of and claims priority fromU.S. application Ser. No. 13/517,337 filed Jul. 9, 2012, and entitledNEW AMINOTETRALINE DERIVATIVES, which is a National Stage Entry ofPCT/EP2010/070194 filed Dec. 20, 2010, entitled NEW AMINOTETRALINEDERIVATIVES, the disclosures of which are hereby incorporated entirelyherein by reference.

BACKGROUND OF THE INVENTION

Dysfunction of the serotonin 5-HT1a receptor (5-HT1a) is thought to playa role in the pathogenesis of various disorders such as pain, anxietyand panic disorders, attention deficit and hyperactivity disorder (ADHD)or depression (see e.g. Savitz, Progress in Neurobiology 2009, 88, pages17-31).

Accordingly, selective serotonin reuptake inhibitors (SSRIs) such asfluoxetine, sertraline, paroxetine or citalopram have had significantsuccess in treating depression and related diseases. However, due totheir indirect mode of action on the serotonin receptors, SSRIsstimulate serotonergic receptors non-selectively and via a significantdelay taking several weeks for the drug to begin reaching its fullpotential. Also, SSRIs require sufficient endogenous serotonin and ingeneral have been found to be effective in only up to about 50-60% ofthe patients.

For this reason, directly acting 5-HT1a agonists have been developed.

Buspirone was possibly the 1^(st) direct 5-HT1a agonist, which wasapproved as a human drug for the treatment of generalized anxietydisorder in the 80^(th). However, the bioavailability of buspirone isvery low; moreover, buspirone is a partial 5-HT1a agonist withremarkable affinity to other receptors such as the dopamine D1 and withan undesirable affinity to adrenergic alpha receptors. There was thusthe need for alternative 5-HT1a agonists.

Gepirone and tandospirone are both partial and selective 5-HT1a agonistswhich share a 4-pyrimidin-2-ylpiperazinylbutyl partial structure withbuspirone. While the approval of gepirone for treating anxiety anddepression was refused by the American Food and Drug Administration in2007, tandospirone is only available in China and Japan for treatinganxiety and major depressive disorder.

8-Hydroxy DPAT is a compound which is known as full 5-HT1a agonists(Arvidsson et al, J Med Chem 1981, Vol 24.8, p 921; Arvidsson et al, JMed Chem 1984, Vol 27.1, p 45). However, the compound has only been usedas a research tool, inter alia because of its very low oralbioavailability (Mason et al, Xenobiotica, 1995, Vol 25.12, p 1371).Also, while 8-OH-DPAT was originally described to have no significantdopaminergic activity it later turned out that the compound also hascertain affinity to the D3 receptor (Lejeune, J Pharmacol Exp Ther 1997,Vol 280.3, p 1241).

Various derivatives of 8-OH-DPAT have been published in the 80^(th) and90^(th) with the aim to improve the pharmacokinetic properties ofaminotetralines. These derivatives are mainly based on a modification ofthe tetraline scaffold such as e.g. annelation to a third ring, leadingto orally available benzindol-8-amino derivatives (Hansson, Eur J MedChem 1997, Vol 32, p 571; Ennis, J Med Chem 1995, Vol 38, p 2217).However, unfortunately this family of benzindoles has been shown to havemutagenic potential by being tested positive in the Ames test(Stjernlöf, J Med Chem 1993, Vol 36, p 2059).

Although various other direct and selective 5-HT1a agonists have beendescribed in literature, none of them have been widely approved forhuman use up to now. Examples are disclosed in WO 03/106449,WO2009/060030, WO 02/83666, WO 02/60423, WO 04/14915, WO 05/90300, WO05/12291, or WO 99/65887.

A need therefore exists to provide alternative 5-HT1a agonists.

Preferably, such 5-HT1a agonists are full agonists showing at leastabout 70%, preferably at least about 80%, more preferably at least about90%, more preferably at least about 95% activity, even more preferablyabout 100% agonist activity compared to serotonin in a functional 5-HT1aassay.

In one instance it may be desirable to have partial agonists at the5-HT1a receptor thus exhibiting between about 30 and about 70%serotonergic activity.

In one instance it is also desirable that such new 5-HT1a ligands areselective 5-HT1a modulators showing significant selectivity to thephylogenetically related dopaminergic and adrenergic receptors. Forexample, in certain instances it would be advantageous if the new 5-HT1aagonists would have a selectivity to at least one, preferably of two,more preferably of all of D1, D2, D3 and D4 receptors of at least afactor 30, more preferably at least a factor 50, and even morepreferably at least a factor of 100, 200 or more.

In contrast, and depending on the disease to be treated it may beadvantageous in certain cases if such new 5-HT1a agonists also exhibitsignificant dopaminergic activity, preferably to the D2 and/or D3receptor. For example, in the treatment of certain movement disordersrelated to the dopaminergic system, a 5-HT1a agonists may be desirablethat also exhibits D2 and/or D3 affinity thus showing an affinity to the5-HT1a receptor with a selectivity to D2 and/or D3 of less than about afactor 30, more preferably less then about a factor 20, or 10.

Desirably, the new 5-HT1a agonists are orally available or can bedelivered through biological membranes such as the skin or mucosa. Forexample, it could be of advantage if the new 5-HT1a agonists can beadministered transdermally, preferably by passive transdermal systemssuch as patches.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a functional representation of the activity of compounds 1 and2 in comparison t o the activity of seretonin at the 5-HT1 receptor;

FIG. 2( a) is a functional representation is a comparison of lickingtime in the mouse formalin assay after the oral administration ofcompound 1 at a 3 mg/kg dose;

FIG. 2( b) is a functional representation is a comparison of lickingtime in the mouse formalin assay after the oral administration ofcompound 1 at a 20 mg/kg dose;

FIG. 3 is an X-ray powder diffraction (XRPD) spectrum of the crystallinebase of compound 1;

FIG. 4( a) depicts pretest and postest means±SEM of “uncontaminatedcircling” times expressed by eight L-DOPA induced Sprague-Dawley ratsper group treated with 1 mg/kg racemicN-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine; and

FIG. 4( b) depicts pretest and postest means±SEM of “uncontaminatedcircling” times expressed by eight L-DOPA induced Sprague-Dawley ratsper group treated with 3 mg/kg racemicN-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment relates to compounds of the general formula I

-   -   wherein    -   the * indicates an asymmetric centre,    -   R is OR1, di(C1-C3)alkylamino, S(C1-C3)alkyl, SH or NHR3;    -   R1 is hydrogen, a group —C(═O)R2, —SO₂CF₃, or (C1-C3)alkyl which        is unsubstituted or substituted with one or more halogen atoms;    -   R2 is (C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl        or phenyl(C1-C3)alkyloxy, wherein the phenyl group is optionally        substituted which one or more substituents selected from        (C1-C3)alkoxy, (C1-C3)alkyl, halogen, or CF₃;    -   R3 is hydrogen, (C1-C3)alkyl, formyl, (C1-C3)alkylcarbonyl,        (C1-C3)alkoxycarbonyl, or (C1-C3)alkylaminocarbonyl;    -   Cy is an aromatic, heteroaromatic or non-aromatic cyclic group        X, Y or Z, wherein    -   X is a 5 or 6 membered aromatic or heteroaromatic ring which is        unsubstituted or substituted with one or two groups R4;    -   Y is a bicyclic aromatic or heteroaromatic ring system which is        unsubstituted or substituted with one to three groups R5 and        which ring system is selected from among

-   -   wherein the bond crossed by a dotted line indicates the        attachment site of the group Y to the aminotetraline scaffold;    -   each R4 and R5 is independently selected from halogen, hydroxyl,        (C1-C6)alkyl, preferably (C1-C3)alkyl, (C1-C6)alkoxy, preferably        (C1-C3)alkoxy, or CF₃, wherein each alkyl or alkoxy may be        substituted with one or more halogens or a hydroxyl group; and    -   Z is adamantyl which is unsubstituted or substituted with methyl        and/or hydroxyl including its enantiomers, solvates and        pharmaceutically acceptable salts.

Surprisingly, it has been found that the compounds disclosed herein havestrong affinity to the 5-HT1a receptor. A summary of the bindingaffinities to the 5-HT1a serotonin and to other related G-proteincoupled receptors is shown in Table 1 further below.

It has also been found, surprisingly, that the selectivity to the othertested receptors, in particular to the dopaminergic receptors can besteered by the appropriate selection and combination of the groups R andCy, as further described herein. This allows the design of desiredfeatures (e.g. highly selective 5-HT1a agonists or combined 5-HT1a/D2/D3agonists) depending on the underlying disease.

In one embodiment, in the compounds of formula I R is OR1.

In one embodiment of the present invention, R is OR1 and R1 is methyl,hydrogen, —SO₂CF₃ or a group —C(═O)R2 wherein R2 is (C1-C6)alkyl,(C1-C6)alkoxy, phenyl, or phenyl(C1-C3)alkyl, wherein the phenyl groupis optionally substituted which one or more substituents selected frommethoxy, methyl, halogen. Preferably, R2 is (C1-C6)alkyl.

In one embodiment of the invention, in the compounds of formula I Cy isa 5 or 6 membered aromatic or heteroaromatic ring which may be selectedfrom the group of phenyl, thienyl, furanyl, imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, pyrazolyl, pyridyl, pyrimidyl, and which ring maybeunsubstituted or substituted with one or two groups R4, as definedfurther above.

In another embodiment of the invention, Cy in formula I is adamantyloptionally substituted with methyl and/or hydroxyl, preferablyunsubstituted adamantyl. In one embodiment, Cy is Z, preferablyadamantly, and R is O(C1-C3)alkyl or S(C1-C3)alkyl, preferably, OMe orSMe.

In another embodiment, Cy in the compounds of formula I is a bicyclicaromatic or heteroaromatic ring system Y which is unsubstituted orsubstituted with one, two or three groups R5 and which ring system isselected from among

-   -   wherein each R5 is independently selected from halogen,        hydroxyl, (C1-C3)alkyl, or (C1-3)alkoxy, wherein each alkyl or        alkoxy may be substituted with a hydroxyl group or one or more        halogens, such as to form e.g. the group CF₃. In one embodiment        R5 is fluoro, bromo, chloro, methyl, ethyl, methoxy, ethoxy,        hydroxymethyl, hydroxyethyl or the group CF₃.

In one embodiment of the invention, Cy in formula I is ferrocenyl.

In one embodiment, Cy is benzofuran or benzthiophen, each of which isoptionally substituted with one to three groups R5. In one embodiment,Cy is benzimidazole optionally substituted with one, two or three groupsR5. In one embodiment, Cy is a pyrazolo[1,5a]pyridine optionallysubstituted with one, two or three groups R5.

One embodiment relates to compounds of formula I, wherein

-   -   R is hydroxyl or (C1-C3)alkoxy, preferably methoxy, and    -   Cy is selected from the group of thienyl, preferably,        thien-2-yl, phenyl, adamantyl, preferably adamant-1-yl,        ferrocenyl, preferably ferrocen-1-yl, and [2.2]paracyclophanyl,        preferably [2.2]paracyclophan-4-yl, wherein the thienyl or        phenyl may independently be unsubstituted or substituted with        one to two groups independently selected from among hydroxyl,        (C1-C3)alkyl, preferably methyl and (C1-C3)alkoxy, preferably        methoxy,    -   including its enantiomers, crystals, solvates and        pharmaceutically acceptable salts.

One preferred embodiment relates to compounds having the general formulaII

-   -   wherein    -   R1 is hydrogen, a group —C(═O)R2, or (C1-C3)alkyl which is        unsubstituted or substituted with one or more halogen atoms;    -   R2 is (C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl        or phenyl(C1-C3)alkyloxy, wherein the phenyl group is optionally        substituted which one or more substituents selected from        (C1-C3)alkoxy, (C1-C3)alkyl, halogen, or CF₃;    -   Cy is a 5 or 6 membered aromatic or heteroaromatic ring selected        from the group of phenyl, thienyl, furanyl, imidazolyl,        1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl, pyridyl, pyrimidyl,        and which ring maybe unsubstituted or substituted with one or        two groups R4;    -   each R4 is independently selected from halogen, (C1-C3)alkyl, or        (C1-C3)alkoxy, wherein each alkyl or alkoxy may be substituted        with one or more halogens or a hydroxyl group, including its        enantiomers, solvates and pharmaceutically acceptable salts.

In one preferred embodiment R in formula I is OR1 and R1 in thecompounds of formula I and II is hydrogen.

In another preferred embodiment, R in formula I is OR1 and R1 in thecompounds of formula I and II represents a group C(═O)R2 wherein R2 is(C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl orphenyl(C1-C3)alkyloxy, wherein the phenyl group is optionallysubstituted which one or more substituents selected from (C1-C3)alkoxy,(C1-C3)alkyl, halogen, or CF₃. Such a group may be cleaved off in vivoby esterases thus releasing the hydroxyl function on the aminotetralinring. Since the hydroxyl function is believed one hand to stronglycontribute both to the high affinity to the 5-HT1a receptor, and to highselectivity over other G-protein coupled receptors but on the other handto potentially negatively impact on bioavailability, such compounds withan ester function in the 8-position may represent valuable prodrugs. Ina preferred embodiment, R2 is (C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, orbenzyl. In one preferred embodiment R2 is (C1-C3)alkyl.

Accordingly, in one embodiment of the present invention R in thecompounds of formula I is OR1 and R1 in the compounds of formula I or IIis selected from hydrogen or a group C(═O)R2, wherein R2 is as describedabove, and preferably represents (C1-C6)alkyl, (C1-C6)alkyloxy, phenyl,or benzyl, wherein the phenyl ring (also as part of the benzyl group)may be unsubstituted or substituted with one or more methoxy, methyland/or halogen.

Compounds of formula I or II with a more lipophilic group in the8-position such as e.g. (C1-C3)alkoxy generally have a slightly inferioraffinity/selectivity compared to those with a hydroxyl group in the8-position but may have certain advantages in bioavailability.

In one embodiment, R is OR1 and R1, also in formula II, is methyl.

In one embodiment in formula I or II, R is OR1 and R1, also in formulaII, is hydrogen or methyl.

In one preferred embodiment, in the compounds of the present disclosure,Cy is thienyl or phenyl which is unsubstituted or substituted with oneor two groups R4, which are selected from halogen, hydroxyl,(C1-C3)alkyl, or (C1-C3)alkoxy, wherein each alkyl or alkoxy may besubstituted with one or more halogen atoms or a hydroxyl group.

In one embodiment,

-   -   (a) Cy in the compounds of formula I or II is thienyl or phenyl        which is unsubstituted or substituted with one or two groups R4,        which are selected from halogen, hydroxyl, (C1-C3)alkyl, or        (C1-C3)alkoxy, wherein each alkyl or alkoxy may be substituted        with one or more halogen atoms (such as e.g. to form the group        CF₃) or a hydroxyl group; and    -   (b) R in formula I is OR1, and R1 in formula I and II may be        hydrogen, methyl or a group C(═O)R2, wherein R2 is (C1-C6)alkyl,        (C1-C6)alkyloxy, phenyl, or benzyl, and preferably represents        (C1-C3)alkyl.

In one embodiment,

-   -   (a) Cy in the compounds of formula I or II is thienyl or phenyl        which is unsubstituted or substituted with one or two groups R4,        which are selected from fluoro, chloro, bromo, hydroxyl, methyl,        ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl,        hydroxymethoxy, hydroxyethoxy, CF₃ or C₂H₂CF₃ and    -   (b) R in formula I is OR1, and R1 in formula I and II may be        hydrogen, methyl or a group C(═O)R2, wherein R2 is (C1-C6)alkyl,        (C1-05)alkyloxy, phenyl, or benzyl, and preferably represents        (C1-C4)alkyl.

In one embodiment, Cy is phenyl which is unsubstituted or substitutedwith one or two groups R4 which are selected from halogen, preferablyfluoro, chloro or bromo, hydroxyl, methyl, methoxy or ethoxy.

In one embodiment Cy is thien-2-yl which is unsubstituted or substitutedwith one group R4 which is selected from (C1-C3)alkyl, halogen or(C1-C3)alkoxy, preferably fluoro, chloro, bromo, hydroxyl, methyl,methoxy or ethoxy.

In one embodiment Cy is unsubstituted thienyl, preferably unsubstitutedthien-2-yl.

One preferred embodiment of the present invention relates to compoundsof formula II in which R1 is hydrogen or methyl and Cy is phenyl orthienyl, preferably thien-2-yl, wherein the phenyl is optionallysubstituted with one or two groups R4 which are independently selectedfrom halogen, (C1-C3)alkyl, (C1-C3)alkoxy, or CF₃.

One preferred embodiment relates to compounds of formula II, wherein R1is hydrogen or a group —C(═O)R2 wherein R2 is (C1-6)alkyl, phenyl, orbenzyl, wherein the phenyl may be optionally substituted as describedfurther above, and Cy is thien-2-yl, preferably unsubstitutedthien-2-yl.

One embodiment relates to the compounds specifically disclosed in theexperimental section of the present invention and particularly in Tables1 and 2 herein.

Preferred compound according to the present invention are

Another preferred embodiment relates to a compound selected from thegroup of

-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    (Compound 1)-   (R)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    (Compound 1a)-   (S)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    (Compound 1b)-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    (Compound 2)-   (R)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    (Compound 2a)-   (S)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    (Compound 2b)-   N-(8-Hydroxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine (Compound    3)-   N-(8-Methoxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine (Compound    4)-   N-[2-(4-Hydroxyphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine    (Compound 5)-   N-[2-(4-Methoxyphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine    (Compound 6)-   N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine    (Compound 7)-   N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine    (Compound 8)-   N-[2-(1-Adamantyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine    (Compound 9)-   N-[2-(1-Adamantyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine    (Compound 10)-   N-(2-Ferrocenylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine    (Compound 11)-   N-(2-Ferrocenylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine    (Compound 12)-   N-(8-Hydroxytetralin-2-yl)-N-[2-([2.2]paracyclophan-4-yl)ethyl]-N-propylamine    (Compound 13), and-   N-(8-Methoxytetralin-2-yl)-N-[2-([2.2]paracyclophan-4-yl)ethyl]-N-propylamine    (Compound 14)

Another preferred embodiment relates to compounds selected from

-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine-   (R)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine-   (S)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine-   (R)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(2-phenylethyl)amine-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-(2-phenylethyl)amine

Other examples of compounds according to the current invention are

-   Acetic acid 7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl    ester-   4-Hydroxybutanoic acid    7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester-   5-Hydroxypentanoic acid    7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester-   Carbonic acid ethyl    7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine-   N-(2-Benzo[b]thienylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine-   N-(2-Benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine-   N-(3-Benzo[b]thienylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine-   N-(3-Benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine-   N-(8-Methylthiotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine-   N-(8-Aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine-   N-(8-Methylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine-   N-(8-Dimethylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine-   7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl formamide-   7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl carbamic acid    ethyl ester

It was found, surprisingly, that compound 1,N-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine, wasactive in an oral animal model of pain (FIG. 1) and is able to penetrateskin in an in vitro skin model of transdermal penetration (Table 4).Accordingly,N-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine and itsderivatives and close analogs disclosed herein are believed to besuitable for oral and/or transdermal administration.

A particularly preferred embodiment relates to the compoundN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,including its individual enantiomers, and pharmaceutically acceptablesalts thereof.

The present disclosure generally relates to the free bases of therespective compounds as well as to pharmaceutically acceptable salts asdefined herein. In some embodiments, the free base may be particularlysuited such as e.g. in transdermal applications. In other embodiments,salts may have certain advantages.

One specific embodiment relates to the base ofN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine, whichmay be in amorphous or crystalline form. In a preferred embodiment, thebase is in crystalline form. In one embodiment, the base is incrystalline form 1 having main XRPD peaks at about 15.27; 16.68; 21.45;23.60 degrees±0.2 deg 2-theta measured using Cu k-alpha radiation(lambda=1.540 Å). In one embodiment, the base ofN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine is incrystalline form 1 having additional XRPD peaks at about 6.56; 15.18;15.38; 17.37; 23.93; 25.17 degrees±0.2 deg 2-theta. In one embodimentthe crystalline base of compound 1 shows most or substantially all ofthe XRPD 2-theta peaks displayed in Table 5 or FIG. 3 herein. In oneembodiment, the melting point of form 1, as determined by DSC, is atabout 97-99° C.

Another embodiment relates to pharmaceutically acceptable salts of thepresently disclosed compounds. Non limiting examples of pharmaceuticallyacceptable salts are given in the definitions of this application.

One embodiment relates to salts of the presently disclosed compounds,which are formed with optically active, enantiomerically pure organicacids. Such enantiopure organic acids may crystallize with oneparticular enantiomeric form of the compounds disclosed herein or withsynthetic precursors/intermediates thereof thus facilitating anenantiomeric separation of the compounds and/or its synthesisintermediates from racemates or other enantiomeric mixtures, as furtherdisclosed in the synthetic part of this application. Examples of suchorganic acids are tartaric acid, dibenzoyltartaric acid and itsderivatives, cinnamoyltartaric acid and its derivatives, mandelic acid,malic acid, camphoric acid, N-acetylphenylalanine, camphorsulfonic acidor cyclic phosphorous acid esters like4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide.

One particular embodiment are salts or cocrystals of (R)-or(S)-N-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine andits intermediates as disclosed in the synthetic part, with enantiopureorganic acids, preferably with (L)- or (D)-tartaric acid, (R,R)- or(S,S)-dibenzoyltartaric acid or cyclic phosphorous acid esters like (R)-or(S)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide,preferably with (R,R)-or (S,S)-O,O-dibenzoyltartaric acid and 4-(R)- or4-(S)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide,respectively. A preferred embodiment is the salt(R)-N-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine(L)-(−)-(R,R)-O,O-dibenzoyltartaric acid, particularly in crystallineform.

Among the individual enantiomers, those compounds in which the carbonatom marked with an * in formula I and II, is in the (R) configurationhave been shown to have a somewhat improved receptor profile compared tothe respective (S) enantiomer, and are thus preferred. Accordingly, oneembodiment relates to compounds, wherein at least about 70%, morepreferably more than about 80%, 90%, 95%, 96%, 97%, 98% or even morethan about 99% of the compound is in the (R)-configuration, i.e. thecorresponding (S) enantiomer is present in less than about 30%, 20%,10%, 5%, 4%, 3%, 2%, or even less then about 1%.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually found in nature with the most abundant isotope(s)being preferred. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, sulphur, fluorine and chlorine such as H², H³, C¹¹,C¹³, C¹⁴, N¹⁵, O¹⁷, O¹⁸, S³⁵, F¹⁸, and Cl³⁶, respectively. Certainisotopic variations of the invention, for example, those in which aradioactive isotope such as H³ or C¹⁴ is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e., H³,and carbon-14, i.e., C¹⁴, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e., H², may afford certain therapeuticadvantages resulting form greater metabolic stability, for example,increased in vivo half-life, reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of the compoundsof the invention can generally be prepared by conventional proceduresusing appropriate isotopic variations of suitable reagents.

Also part of the invention are those compounds wherein at least one atomhas been replaced by an isotope of a different atom that can be used invivo imaging techniques such as SPECT or PET. Examples for suchderivatives usable in SPECT studies are compounds wherein a Tc^(99m),In¹¹¹, Rb⁸², Cs¹³⁷, I¹²³, Ga⁶⁷, Ir¹⁹² or Tl²⁰¹, and preferably I¹²³ hasbeen introduced (for iodination see e.g.: “Radioiodination Reactions forPharmaceuticals, Compendium for Effective Synthesis Strategies” byCoenen HH, Springer, Dordrecht 2006), while for PET applications C¹¹,N¹³, O¹⁵, F¹⁸, Rb⁸², Sr⁸², and preferably F¹⁸ (“Fluorine-18 labelingmethods: Features and possibilities of basic reactions” by Coenen, HH,Ernst Schering Res Found Workshop 2007, Vol 62, p 15-50; Miller, P W AngChem Int Ed 2008, Vol 47, p 8998) may be used.

The compounds of the present disclosure can be used in therapy,particularly in human therapy.

For the administration as a medicinal drug, the compounds may be used inpharmaceutical composition comprising a compound of the presentdisclosure, and a pharmaceutically acceptable carrier, as furtherdefined herein. Such a pharmaceutical composition can be adapted forexample for oral, intravenous, intramuscular, subcutaneous, nasal,rectal, buccal or transdermal administration and may comprisepharmaceutically acceptable carriers, adjuvants, diluents, stabilizersand the like.

For instance, the compounds of the present invention may be dissolved inoils, propylene glycol or other solvents which are commonly used toproduce an injection. Suitable examples of the carriers include, but notlimited to, physiological saline, polyethylene glycol, ethanol,vegetable oils, isopropyl myristate, etc. The compounds of the presentinvention may be formulated into injections by dissolving, suspending oremulsifying in water-soluble solvent such as saline and 5% dextrose, orin water-insoluble solvents such as vegetable oils, synthetic fatty acidglyceride, higher fatty acid esters and propylene glycol. Theformulations of the invention may include any of conventional additivessuch as dissolving agents, isotonic agents, suspending agents,emulsifiers, stabilizers and preservatives.

In one embodiment, the compounds of the present invention may beadministered orally, e.g. in the form of a tablet, a capsule, a drage',a powder, a granulate, or in form of a liquid or a semi-solid, by way ofnon-limiting example.

Oral formulations may contain, without limitation, sustained releaseagents, disintegrants, fillers, lubricants, stabilizers, antioxidants,flavours, dispersion agents, electrolytes, buffers, dyes, orconservation agents. Suitable excipients and formulations are known tothose skilled in the art and are disclosed in standard monographs suchas like Remington (“The science and practice of pharmacy”, Lippincott,Williams & Wilkins, 2000). Typical sustained release agents are forexample those that swell upon contact with water such aspolyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose,other cellulose ethers, starch, pregelatinised starch, polymethacrylate,polyvinylacetate, microcrystalline cellulose, dextrans, and mixtures ofthese. Non-limiting examples of disintegrants include pregelatinisedstarch, sodium starch glycolate, microcrystalline cellulose,carboxymethylcellulose sodium (CMC-Na), cross-linked CMC-Na, andlow-substituted hydroxypropylcellulose, as well as mixtures thereof.Suitable fillers and binders include without limitation microcrystallinecellulose, powdered cellulose, lactose (anhydrous or monohydrate),compressible sugar, starch (e.g. corn starch or potato starch),pregelatinised starch, fructose, sucrose, dextrose, dextrans, othersugars such as mannitol, maltitol, sorbitol, lactitol and saccharose,siliconised microcrystalline cellulose, calcium hydrogen phosphate,calcium hydrogen phosphate dihydrate, dicalciumphosphate dihydrate,tricalciumphophate, calcium lactate or mixtures thereof. Lubricants,antiadherents and/or glidants include stearic acid, magnesium stearate,calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil,hydrogenated castor oil, sodium stearyl fumarate, macrogols, glyceroldibehenate, talc, corn starch, silicon dioxide, and the like, includingmixtures.

In a preferred embodiment, the compounds are administered transdermally.This mode of administration prevents the so-called 1^(st) pass effect oforal administration and moreover allows providing more constant plasmalevels which is of particular advantage in some instances. The design oftransdermal systems such as e.g. patches or electrophoretic devices isgenerally known from the art, see e.g. Venkatraman and Gale,Biomaterials 1998, Vol 19, p 1119; Prausnitz and Langer, NatBiotechnology 2008, Vol 26.11 p 1261; WO 2001/47503; WO2009/000262;WO99/49852; WO 07/094,876.

Accordingly, one embodiment relates to pharmaceutical compositionscomprising the compounds disclosed herein, wherein the pharmaceuticalcomposition is a transdermal system, and preferably is a patch, such ase.g. of the monolithic “drug-in-adhesive” or of the reservoir type.

In a particularly preferred embodiment of the present disclosure, thetransdermal patch comprisesN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,preferably enantiopure in the form of its (R)-enantiomer, either as thefree base or as a pharmaceutically acceptable salt.

The preferable dose level of the compounds according to the presentinvention depends upon a variety of factors including the condition andbody weight of the patient, severity of the particular disease, dosageform, and route and period of administration, but may appropriately bechosen by those skilled in the art. In various embodiments, thecompounds are administered in an amount ranging from 0.001 to 10 mg/kgof body weight per day, or from 0.03 to 1 mg/kg of body weight per day.Individual doses may range from about 0.1 to 100 mg of active ingredientper day, from about 0.2 to 50 mg/day, or from about 0.3 to 20 mg/day.Doses may be administered once a day, or several times a day with eachdivided portions.

Another aspect of the present invention is a Kit comprising a medicineor a pharmaceutical composition as described above, and instructions forits use.

The medicine according to the present invention may comprise one of thepresently disclosed compounds as “stand alone” treatment of a CNSdisease. Alternatively, a presently disclosed compound may beadministered together with other useful drugs in a combination therapy.In a non-limiting example, a compound according to the present inventionis combined with another antidepressant medicament having a differentmode of action. Likewise a compound of the present invention can becombined with an analgesic drug if a painful condition is to be treated.Also, a compound of the present disclosure may be used in combinationwith levodopa to treat Parkinson's disease and levodopa-associateddyskinesia. In combination therapies the two or more active principlesmay be provided via the same formulation or as a “kit of parts”, i.e. inseparate galenic units. Also, the two or more active principles may beadministered to the patient at the same time or subsequently, e.g. in aninterval therapy.

The compounds of the present invention are useful medicines, and may beused for the treatment and/or prevention of various diseases of the CNSsystem. One embodiment of the present disclosure is thus a compound asdescribed herein for use as a medicine, in particular for use as amedicine for the treatment and/or prevention of a disease which isassociated with a malfunction of the serotonin signaling system,examples of which are further disclosed below.

Because of their affinity to the serotonin 5-HT1a receptors, the presentcompounds in one embodiment can be used for the production of amedicament for the treatment or prevention of a variety of diseases suchas

-   -   Pain, particularly chronic pain (nociceptive and neuropathic),        including for example        -   neuropathic pain (central and peripheral) including            mononeuropathies such as trigeminal neuralgia, and            polyneuropathies, which may be associated with diseases such            as diabetic neuropathy, herpetic or other infections, AIDS,            or cancer        -   postoperative pain        -   inflammatory pain    -   treatment and prophylaxis of migraine    -   depression, such as for example        -   endogenic depressions including major depression and            depressive phases of bipolar disorders        -   somatogenic depressions        -   psychogenic depressions    -   anxiety disorders, such as generalized anxiety, panic disorders,        certain kinds of phobia such as e.g. social phobia, and        post-traumatic disorders    -   compulsive disorders and/or aggressive disorders    -   a psychotic disease including manic phases of bipolar disorder,        acute idiopathic psychotic illnesses, psychoses associated with        other diseases, drug-induced psychoses, and particularly        schizophrenia;    -   attention deficit hyperactivity disorder (ADHD);    -   movement disorders, including        -   idiopathic movement disorders such as e.g. idiopathic            Parkinson's disease and it's associated motor disturbances            such as tremors, akinesia, and dyskinesia; Segawa syndrome;            or Tourette's syndrome        -   drug-induced movement disorders, such as e.g. tardive            dyskinesia or, particularly, levodopa-induced dyskinesia;    -   addiction disorders such as e.g. cocaine, alcohol, opiate and        nicotine addiction;    -   sexual dysfunction, in particular male or female sexual response        disorders, such as, particularly, male impotence;    -   amnesic and/or cognitive disorders,    -   autism, or disorders associated with autism;    -   stroke;    -   urinary incontinence; and/or    -   sleep disorders.

A further therapeutic application that can be mentioned is the treatmentand/or prevention of neurodegenerative diseases, since due to theneuroprotective effect of 5-HT1a agonists, the substances may delay orstop the destruction or loss of neurones as the cause or result of apathophysiological episode. Such illnesses are for example amyotrophiclateral sclerosis, Alzheimer's disease, Huntington's chorea, epilepsy,Parkinson's disease or other synucleopathies, such as e.g. of theParkinson-plus-syndrome type.

Another embodiment of the present disclosure is a method of treating asubject having a disease as described above by administering a compoundas described herein in a therapeutically effective amount. According toone aspect, the subject to be treated with the presently disclosedcompounds is determined to be in need of a treatment of one or more ofthe above diseases based on a prior diagnosis of the disease or variousdiseases.

Definitions

“Adamantyl” refers to the radical of adamantane(tricyclo[3.3.1.1^(3,7)]decan)

“Alkyl” includes monovalent saturated aliphatic hydrocarbyl groups. Thehydrocarbon chain may be either straight-chained or branched. Examplesof “alkyl” include those with 1-6 carbon atoms (“(C1-C6)alkyl”), thosewith 1-5 carbon atoms (“(C1-C5)alkyl”), 1-4 carbon atoms(“(C1-C4)alkyl”), or only 1-3 carbon atoms (“(C1-C3)alkyl”). This termis exemplified by groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, iso-butyl, tert-butyl, t-amyl, and the like.

“Alkylaminocarbonyl” refers to the group —C(═O)—NH-alkyl, wherein alkylis defined above.

“Alkylcarbonyl” includes the group —C(═O)-alkyl, wherein alkyl isdefined above.

“Alkyloxycarbonyl” refer to the radical —C(═O)—O13 R, wherein R is analkyl group as defined herein. In various embodiments,“alkyloxycarbonyl” is a (C1-C6)alkyloxycarbonyl group,(C1-C5)alkyloxycarbonyl group or a (C1-C3)alkyloxycarbonyl group.

“Alkyloxy” or “alkoxy” includes the group —OR wherein R is “alkyl” asdefined and exemplified further above. Particular alkyloxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, 1,2-dimethylbutoxy, andthe like.

“Dialkylamino” refers to the group —N-dialkyl, where “dialkyl” indicatestwo independent alkyl groups (defined above) bonded to the N atom. Anon-limiting example of “dialkylaminocarbonyl” is —N-di(C1-C3)alkyl,wherein two individual alkyl groups each of up to three C-atoms arebound to the nitrogen atom.

“Formyl” refers to the group —CH═O

“Furanyl” refers to the aromatic heterocyclic radical of furane (C₄H₄O;oxacyclopentadiene)

“Halo” or “halogen” refers in particular to fluoro, chloro, bromo andiodo. Preferred halogen groups are either fluoro or chloro.

“Heteroaromatic” refers to an aromatic heterocycle, as defined herein.Whether a heteroaromatic group is substituted with one or moresubstituents, is specified throughout this specification and in theitems.

“Heterocycle” refers to a compound comprising at least one cycle inwhich a ring forming atom is different from carbon.

“Hydroxyl” refers to the radical —OH.

“Imidazolyl” refers to the aromatic heterocyclic radical of imidazole(C₃H₄N₂; 1,3-diaza-2,4-cyclopentadiene).

“Phenyl” is the aromatic radical —C₆H₅.

“Phenoxy” or “Phenyloxy” comprises the group —O-phenyl, wherein “phenyl”has the meaning as defined further above.

“Phenylalkyl” is an “alkyl” group substituted with a phenyl group,wherein “alkyl” is as defined further above. For example,phenyl(C1-C6)alkyl refers to a (C1-C6)alkyl which is substituted with aphenyl group. Examples of phenylalkyl groups are phenylethyl and benzyl,wherein benzyl is a particularly preferred phenylalkyl group.

“Phenylalkyloxy” is an “alkyloxy” group substituted with a phenyl.Examples of phenylalkyloxy groups are phenylethyloxy and benzyloxy.

“Pyrazolyl” refers to the radical of pyrazole (C₃H₄N₂; 1,2-diazole).

“Pyridyl” refers to the radical of pyridine (C₅H₅N; azabenzene)

“Pyrimidinyl” refers to the radical of pyrimidine (C₄H₄N₂; 1,3 diazine)

“Thienyl” is the aromatic heterocyclic radical —C₄H₃S of thiophene(C₄H₄S; thiacyclopentadiene).

“Triazolyl” refers to aromatic heterocyclic radical with the molecularformula C₂H₂N₃, having a five-membered ring of two carbon atoms andthree nitrogen atoms.

“1,2,3-Triazolyl” and “1,2,4-triazolyl” refer to triazolyl residues,with the numbers specifying the positons of the N-atoms in therespective ring.

Unless expressly specified otherwise, any “alkyl”, “phenyl”,“heteroaryl”, “furanyl”, pyrazolyl” etc is meant to be unsubstituted. Ifany “alkyl”, “phenyl”, or “heteroaryl”, is expressly stated to besubstituted in a given substituent, this usually also refers to therespective “alkyl”, “phenyl”, or “heteroaryl” partial structures of morecomplex structures in the same substituent, such as “alkyloxy”,“alkylsulfonyl”, “phenoxy”, “heteroaryloxy”, etc.

In the present disclosure, a compound is thought to be “enantiomericallypure” or “enantiopure” if at least about 95%, preferably at least about96%, 97%, 98%, even more preferably at least about 99% of the compoundconsists of a particular enantiomer, such as e.g. the (R)-enantiomerwhile the other enantiomer, such as e.g. the (5) enantiomer is presentin less than about 5%, 4%, 3%, 2%, or even less than about 1%.

“Pharmaceutically acceptable” means generally considered as safe for usein pharmaceutical preparations, and preferably officially approved by aregulatory agency of the Federal or a state government for such use,such as e.g. by the US Food and Drug Administration (FDA), or theEuropean medicine Agency (EMEA), and/or being listed in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, and muconic acid. Other saltsinclude 2,2-dichloroacetate, adipate, alginate, ascorbate, aspartate,2-acetamidobenzoate, caproate, caprate, camphorate, cyclamate,laurylsulfate, edisilate, esylate, isethionate, formate, galactarate,gentisate, gluceptate, glucuronate, oxoglutarate, hippurate,lactobionate, napadisilate, xinafoate, nicotinate, oleate, orotate,oxalate, palmitate, embonate, pidolate, p-aminosalicylate, sebacate,tannate, rhodanide, undecylenate, and the like; or (2) salts formed whenan acidic proton present in the parent compound is replaced, such aswith ammonia, arginine, benethamine, benzathine, calcium, choline,deanol, diethanolamine, diethylammonium, ethanolamine, ethylendiamine,meglumine, hydrabamine, imidazole, lysine, magnesium,hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium,trolamine, tromethamine or zinc.

“Pharmaceutically acceptable carrier” refers to a diluent, adjuvant,excipient, or carrier, or other ingredient with which a compound of theinvention is administered and which is pharmaceutically acceptable asfurther defined herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Subject” includes humans. The terms “human,” “patient” and “subject”are used interchangeably herein.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” can vary depending on the compound, the disease and itsseverity, and the condition, age, weight, gender etc. of the subject tobe treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least reducing one of theclinical symptoms of the disease). In another embodiment “treating” or“treatment” refers to ameliorating at least one physical parameter,which may or may not be discernible by the subject. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically (e.g. stabilization of a discernible onnon discernible symptom), physiologically (e.g. stabilization of aphysiological parameter), or both. In yet another embodiment, “treating”or “treatment” refers to delaying or preventing the onset or progressionof the disease or disorder.

Specific Items of the Invention

Specific embodiments of the inventions are the items 1-28 listed below.These items are non-limiting examples to further illustrate theinvention, but shall not limit the disclosure and the scope of thepresent invention.

Items

Item 1—A compound of formula I

-   -   wherein    -   R is OR1, di(C1-C3)alkylamino, SH, S(C1-C3)alkyl or NHR3;    -   R1 is hydrogen, a group —C(═O)R2, —SO₂CF₃, or (C1-C3)alkyl which        is unsubstituted or substituted with one or more halogen atoms;    -   R2 is (C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl        or phenyl(C1-C3)alkyloxy, wherein the phenyl group is optionally        substituted with one or more substituents selected from        (C1-C3)alkoxy, (C1-C3)alkyl, halogen, or CF₃;    -   R3 is hydrogen, (C1-C3)alkyl, formyl, (C1-C3)alkylcarbonyl,        (C1-C3)alkoxycarbonyl, or (C1-C3)alkylaminocarbonyl;    -   Cy is an aromatic, heteroaromatic or non-aromatic cyclic group        X, Y or Z, wherein    -   X is a 5 or 6 membered aromatic or heteroaromatic ring which is        unsubstituted or substituted with one or two groups R4;    -   Y is a bicyclic aromatic or heteroaromatic ring system which is        unsubstituted or substituted with one to three groups R5 and        which ring system is selected from among

-   -   wherein the bond crossed by a dotted line indicates the        attachment site of the group Y to the aminotetraline scaffold;    -   wherein each R4 and R5 is independently selected from halogen,        hydroxyl, CF₃, C1-C3 alkyl, or C1-C3 alkoxy, wherein each alkyl        or alkoxy may be substituted with one or more halogens or a        hydroxyl group, and Z is adamantyl which is unsubstituted or        substituted with methyl and/or hydroxyl; and    -   including its enantiomers, crystals, solvates and        pharmaceutically acceptable salts.

Item 2—A compound according to item 1, wherein R is OR1.

Item 3—A compound according to item 2, wherein R1 is methyl, hydrogen ora group —C(═O)R2 wherein R2 is (C1-C6)alkyl or (C1-C6)alkyloxy,preferably (C1-C6)alkyl.

Item 4—A compound according to anyone of the preceding items wherein Cyis a 5 or 6 membered aromatic or heteroaromatic ring which is selectedfrom the group of phenyl, thienyl, furanyl, imidazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, pyrazolyl, pyridyl, pyrimidyl, and unsubstituted orsubstituted with one or two groups R4.

Item 5—A compound according to items 1-4, wherein Cy is unsubstitutedadamantyl, preferably adamant-1-yl.

Item 6—A compound according to items 1-4, wherein Cy is a bicyclicaromatic or heteroaromatic ring system Y which is unsubstituted orsubstituted with one to three groups R5 and which ring system isselected from among

-   -   wherein each R5 is independently selected from halogen,        hydroxyl, CF₃, (C1-C3)alkyl, or (C1-C3)alkoxy, wherein each        alkyl or alkoxy may be substituted with one or more halogens or        a hydroxyl group.

Item 7—A compound having the general formula II

-   -   wherein    -   R1 is hydrogen, a group —C(═O)R2, or (C1-C3)alkyl which is        unsubstituted or substituted with one or more halogen atoms,    -   R2 is (C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl        or phenyl(C1-C3)alkyloxy, wherein the phenyl group is optionally        substituted with one or more substituents selected from        (C1-C3)alkoxy, (C1-C3)alkyl, halogen or CF₃,    -   Cy is a 5 or 6 membered aromatic or heteroaromatic ring selected        from the group of phenyl, thienyl, furanyl, imidazolyl,        1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl, pyridyl, pyrimidyl,        each of which is unsubstituted or substituted with one or two        groups R4,    -   each R4 is independently selected from halogen, (C1-C3)alkyl, or        (C1-C3)alkoxy, wherein each alkyl or alkoxy may be substituted        with one or more halogens or a hydroxyl group,    -   including its enantiomers, crystals, solvates and        pharmaceutically acceptable salts.

Item 8—A compound according to item 7, wherein R1 is hydrogen or a group—C(═O)R2 wherein R2 is (C1-C6)alkyl or (C1-C6)alkyloxy, preferably(C1-C3)alkyl.

Item 9—A compound according to item 7, wherein R1 is methyl.

Item 10—A compound according to items 1-3 or 7, wherein Cy is thienyl orphenyl which is unsubstituted or substituted with one or two groups R4,which are selected from halogen, hydroxyl, (C1-C3)alkyl, or(C1-C3)alkoxy, wherein each alkyl or alkoxy may be substituted with oneor more halogen atoms or a hydroxyl group.

Item 11—A compound according to items 1-3 or 7, wherein Cy is phenylwhich is unsubstituted or substituted with one or two groups R4 whichare selected from halogen, methyl, hydroxy, methoxy or ethoxy.

Item 12—A compound according to items 1-3 or 7, wherein Cy is thien-2-ylwhich is unsubstituted or substituted with one group R4 which isselected from (C1-C3)alkyl, halogen, (C1-C3)alkoxy.

Item 13—A compound according to items 1-3 or 7, wherein Cy isunsubstituted thienyl, preferably unsubstituted thien-2-yl.

Item 14—A compound according to items 1-3 or 7, wherein R1 is hydrogenor methyl and Cy is phenyl or thienyl, preferably thien-2-yl, whereinthe phenyl is optionally substituted with one or two groups R4 which areindependently selected from halogen, hydroxyl, (C1-C3)alkyl,(C1-C3)alkoxy, or CF3.

Item 15—A compound according to item 7, wherein R1 is hydrogen or agroup —C(═O)R2 wherein R2 is (C1-C6)alkyl, and Cy is thien-2-yl,preferably unsubstituted thien-2-yl.

Item 16—A compound according to item 1, wherein

-   -   R is hydroxyl or (C1-C3)alkoxy, preferably methoxy, and    -   Cy is selected from the group of thienyl, preferably,        thien-2-yl, phenyl, adamantyl, preferably adamant-1-yl,        ferrocenyl, preferably ferrocen-1-yl, and [2.2]paracyclophanyl,        preferably [2.2]paracyclophan-4-yl, wherein the thienyl or        phenyl may independently be unsubstituted or substituted with        one to two groups independently selected from among hydroxyl,        (C1-C3)alkyl, preferably methyl and (C1-C3)alkoxy, preferably        methoxy,    -   including its enantiomers, crystals, solvates and        pharmaceutically acceptable salts.

Item 17—A compound according to item 16, and selected from

-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,-   (R)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,-   (S)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,-   (R)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,-   (S)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,-   N-(8-Hydroxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine,-   N-(8-Methoxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine,-   N-[2-(4-Hydroxyphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine,-   N-[2-(4-Methoxyphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine,-   N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine,-   N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine,-   N-[2-(1-Adamantyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine,-   N-[2-(1-Adamantyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine,-   N-(2-Ferrocenylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine, and-   N-(2-Ferrocenylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine,    -   including its enantiomers, crystals, solvates and        pharmaceutically acceptable salts.

A compound according to item 1 and selected from

-   Acetic acid 7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl    ester,-   4-Hydroxybutanoic acid    7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester,-   5-Hydroxypentanoic acid    7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester,-   Carbonic acid ethyl    7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester,-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine,-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine,-   N-(2-Benzo[b]thienylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine,-   N-(2-Benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine,-   N-(3-Benzo[b]thienylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine,-   N-(3-Benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine,-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine,-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine,-   N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine,-   N-(8-Methoxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine,-   N-(8-Methylthiotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine,-   N-(8-Aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine,-   N-(8-Methylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine,-   N-(8-Dimethylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine,-   7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl formamide, and-   7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl carbamic acid    ethyl ester    -   including its enantiomers, crystals, solvates and        pharmaceutically acceptable salts.    -   1)        N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine        including its enantiomers, crystals solvates and        pharmaceutically acceptable salts.    -   2) A salt of        N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine        and an enantiomerically pure organic acid, preferably tartaric        acid or dibenzoyltartaric acid.    -   3) The base        N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine    -   4) A compound according to anyone of the preceding items, and        particularly the compounds of items 19, 20, and 21, wherein at        least 90% of the compound is in the (R)-configuration.    -   5) A compound according to anyone of the preceding items for use        in therapy.    -   6) A pharmaceutical composition comprising at least one compound        according to anyone of the preceding items and a        pharmaceutically acceptable carrier.    -   7) A pharmaceutical composition according to item 24 adapted for        oral or transdermal administration.    -   8) The pharmaceutical composition of item 25, which is a        transdermal patch.    -   9) The transdermal patch of item 26 comprising        N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine        or a pharmaceutically acceptable salt thereof    -   10) Use of a compound according to anyone of items 1-22 for        preparing a medicament for the treatment of a disease of the        central nervous system, preferably of a disease which is        associated with the disturbance of the serotonergic        transmission.    -   11) Use according to item 28, wherein the disease is depression,        an anxiety or panic disorder, attention deficit hyperactivity        disorder (ADHD), sleep disorder, pain, a sexual disorder, or a        movement disorder.    -   12) Use according to item 29, wherein the movement disorder is        L-DOPA associated dyskinesia.        III. Experimental Part        A. Synthesis        1. General Synthesis Schemes

A compound of formula I can be synthesized starting from 2-tetraloneswhich are substituted in position 8 according to formula A1. Reductiveamination of compounds of A1 utilizing propylamine and a hydridetransferring reagent like sodium triacetoxyborohydride gives thesecondary amines of formula A2 in good yields.

Subsequent acylation of compounds of formula A2 results in amidsaccording to formula A4. For this coupling reaction the acid derivativesaccording to formula A3 are used in an activated form as acid chlorides,acid bromides or acid anhydrids or, alternatively, as free acidcompounds in the presence of an appropriate activating reagent typicallyused for amid coupling

-   -   wherein W is selected of hydroxyl, chloro, bromo or        alkylcarbonyloxy;    -   and if W is hydroxyl, the corresponding acid derivative is        activated by addition of an acid specific activating reagent        like hydroxybenzotriazole, hydroxyazabenzotriazole, HATU        (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate) or TBTU (O-benzotriazolyl        tetramethylisouronium tetrafluoroborate).

Reduction of the amid group of the compounds according to formula A4 inthe presence of a reductive agent like lithium aluminiumhydride resultsin derivatives of formula A5 which represent the final compounds asembodiments of this disclosure

-   -   and wherein in anyone of the formulas I, A1, A2, A3, A4 and A5    -   R and Cy are as defined further above and in the disclosures for        compounds of formula I.

If R represents OR1 and if the final compounds shall be substituted byan 8-OH group (e.g. formula I; R=OH) a cleavage reaction with a compoundaccording to formula A6 must be done. For example the acidic hydrolysisof an alkyloxy group in compound A6 (when R1=(C1-C3)alkyl) using strongmineralic acids like HBr, HCl, H₁ or H₂SO₄ or borohalide type Lewisacids like BCl₃ or BBr₃ reveals in the formation of compounds accordingto formula A7 representing further final compounds as embodiments ofthis disclosure

-   -   wherein R1 and Cy are as defined further above and in the        disclosures for compounds of formula I.

The synthesis of the enantiomerically pure embodiments starts from theracemic secondary amines according to formula A2 which are reacted withenantiochemically pure acids like (L)- or (D)-tartaric acid, (R,R)- or(S,S)-dibenzoyltartaric acid and its derivatives, (R,R)- or(S,S)-cinnamoyltartaric acid and its derivatives, (L)- or (D)-mandelicacid, (L)- or (D)-malic acid, (L)- or (D)-camphoric acid, (L)- or(D)-N-acetylphenylalanine, (L)- or (D)-camphorsulfonic acid or cyclicphosphorous acid esters like 4-(R)- or4-(S)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxideto form diastereomeric salts. Stereochemical resolution of the resultingdiastereomeric salts and subsequent liberation of the free base underbasic conditions yields in the enantiopure secondary amines R-(A2) andS-(A2) according to formula A2a.

Subsequent reaction of the enantiomerically pure compounds R-(A2) orS-(A2) as described in detail above results in the formation ofenantiopure compounds according to formula I representing finalcompounds as embodiments of this disclosure

-   -   and wherein in anyone of the formulas I and A2a R and Cy are as        defined further above and in the disclosures for compounds of        formula I.        2. Synthesis of the Individual Compounds        2a. Synthesis of Secondary Amines According to Formula A2

The secondary amines of formula A2 were synthesized by reductiveamination reaction of 8-substituted 2-tetralone derivatives according toformula A1 with n-propylamine. Reduction was accomplished in thepresence of sodium triacetoxyborohydride in dry methylenchloride assolvent. The reaction was terminated by adding hydrochloric acid and theresulting amino hydrochloride was extracted from the aqueous phase underbasic conditions and finally precipitated as hydrochloride to receivethe secondary amines of type A2 in good yields with more than 75% yield.

N-(8-Methoxytetralin-2-yl)-N-propylamine Hydrochloride (A2-1: R=OMe)

To a solution of 5.1 g 8-methoxy-2-tetralone (A1-1: R=OMe) (purchasedfrom Sigma-Aldrich, Munich (Germany); order number: 535451) (30 mmol)and 17 g NaBH(OAc)₃ (81 mmol) in 80 mL dry CH₂Cl₂ 4.9 mL n-Propylamin(59 mmol) were added dropwise. After stirring for 25 hrs at roomtemperature the solvent was evaporated, the residue resolved in conc.HCl and washed for several times with diethyl ether. The aqueous phasewas basified with 5N NaOH and extracted with diethyl ether for severaltimes, the collected organic layers were dried over Na₂SO₄ and thesolvent was concentrated. Addition of 20 mL 2 M HCl (40 mmol) in diethylether and cooling at 4° C. resulted in precipitation of the hydrochloricsalt, which was filtered and dried in vacuo to get a white solid.

Yield: 5.8 g (76%).

MP: 181° C. (literature: 191-193° C., for reference see: Naiman et al. JMed Chem 1989, Vol 32, p 253).

MS (EIMS): m/z 219 (M)⁺. IR (NaCl) ν (cm⁻¹): 3394, 2927, 1585, 1466,1254, 1026 (free base). ¹H NMR (CD₃OD, 600 MHz) δ (ppm): 1.07 (t, J=7.5Hz, 3 H), 1.74-1.84 (m, 3 H), 2.31 (m, 1 H), 2.59 (dd, J=16.6 Hz, 10.4Hz, 1 H), 2.87-2.97 (m, 2 H), 3.10 (m, 2 H), 3.29-3.34 (m, 1 H), 3.48(m, 1 H), 3.82 (s, 3 H), 6.72 (d, J=7.7 Hz, 1 H), 6.77 (d, J=8.1 Hz, 1H), 7.13 (dd, J=8.1 Hz, 7.7 H). ¹³C NMR (CD₃OD, 90 MHz) δ (ppm): 11.3,21.0, 26.8, 27.4, 28.6, 47.8, 55.8, 56.0, 108.6, 121.8, 128.4, 137.2,158.6.

HR-MS: C₁₈H₂₁ClFN₃OS; calculated: 381.1078; found: 381.1075.

The enantiomerically pure secondary amines of type (R)-A2 and (S)-A2could be synthesized by reaction with 4-(R)- or4-(S)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxidein ethanol resulting in formation of a diastereomeric salt, which wasseparated and crystallized in isopropanol. Liberation of the enantiopuresecondary amines according to formula (R)-A2 and (S)-A2 was achieved bytreatment with an aqueous solution of potassium hydroxide and extractionwith methylenehloride. Alternatively, (R)-A2 could also be prepared byutilizing the enantiomerically pure (R,R)-O,O-dibenzoyl tartaric acid inethanol.

(R)-N-(8-Methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe)

To a solution of 720 mg (2.6 mmol)4-(R)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxidein 30 mL EtOH a solution of 570 mg (2.6 mmol) racemicN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) (as the freebase) in 15 mL EtOH was added and stirred for 40 min at roomtemperature. After evaporation of the solvent in vacuo the residue wasresuspended in 25 mL of acetone and heated until reflux for 40 min. Thesolution was cooled down and stored at 4° C. for 20 hrs. The precipitatewas recrystallized twice from isopropanol and dried to get the saltconsisting of (R)-N-(8-methoxytetralin-2-yl)-N-propylamine and4-(R)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide.

Yield: 150 mg of a white solid (12%).

[α]_(D) ²⁵=+63.6° (in MeOH).

To liberate the free base (R)-N-(8-methoxytetralin-2-yl)-N-propylamine140 mg of diastereomeric salt were dissolved in an aqueous solution ofKOH and extracted for several times with methylenehloride. The organiclayers were dried over Na₂SO₄, the solvent was evaporated in vacuo andthe resulting residue was dried in vacuo to yield pure(R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe).

Yield: 58 mg of a yellow oil (91%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A2-1.

[α]_(D) ²³=+80.1° (in MeOH).

Alternatively, to a solution of 160 mg (0.72 mmol) racemicN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) (as the freebase) in 1.0 mL EtOH were added a solution of 270 mg (0.72 mmol) of(L)-(−)-O,O-(R,R)-dibenzoyltartaric acid monohydrate in 2.0 mL EtOH andstirred for 10 min at room temperature to get a fine white precipitate,which was filtered, washed with cold ethanol and suspended in 10% (v/v)aqueous KOH. After the extraction of the aqueous layer withmethylenehloride for four times the organic layers were dried overNa₂SO₄, the solvent was evaporated in vacuo to get(R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe).

Yield: 130 mg of a yellow oil (82%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A2-1.

[α]D²³=+67.0° (in MeOH).

(S)-N-(8-Methoxytetralin-2-yl)-N-propylamine ((S)-A2-1: R=OMe)

Synthesis worked similar according to the preparation of (R)-A2-1 whenusing4-(S)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxideto get the diasteromeric salt consisting of(S)-N-(8-methoxytetralin-2-yl)-N-propylamine and4-(S)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide.

[α]_(D) ²⁵=−54.2° (in MeOH).

Liberation of the pure (S)-N-(8-methoxytetralin-2-yl)-N-propylamine((S)-A2-1: R=OMe) could be achieved according to the protocol which isdescribed for the liberation of(R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe).

Yield: 340 mg of a colorless oil (17%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A2-1.

[α]_(D) ²³=−70.9° (in MeOH).

2b. Synthesis of Amides According to Formula A4

The formation of the amides according to formula A4 was achieved bycoupling the secondary amine A2 with the acid chloride of an appropriateacid derivative of formula A3 (W=Cl) in dry chloroform in the presenceof triethylamine as a base. If the secondary amine was provided as ahydrochloric salt, the free base had to be liberated before coupling.

Alternatively, if necessary, the coupling reaction could be achieved byusing the free acid derivative according to formula A3 (W=OH), which wasdissolved in DMF in the presence of diisopropylethylamine (DIPEA) andwhich was furthermore activated by the reagentO-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU).

Most of the applied acid derivatives according formula A3 can bepurchased from established suppliers of fine chemicals for synthesis. Ifnot stated otherwise all acid derivatives of this invention werepurchased from Acros Organics, Geel (Belgium), Alfa Aesar, Karlsruhe(Germany), Maybridge, Tintagel, Cornwall (UK) or Sigma-Aldrich, Munich(Germany).

N-(8-Methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide (A4-1: R=OMe,Cy=2-thienyl)

A solution of 60 mg (0.27 mmol) of the free base ofN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) and 0.11 mL Et₃N (0.79mmol) in 5 mL dry CHCl₃ was cooled in an ice bath. After adding 0.05 ml(0.41 mmol) 2-thienylacetic acid chloride (A3-1: W=Cl, Cy=2-thienyl) tothe mixture the ice bath was removed and the reaction was stirred for 2hrs at room temperature. In a second step further 0.05 mL (0.41 mmol) of2-thienylacetic acid chloride (A3-1) were added and the reaction stirredfor 20 hrs. The mixture was washed with a saturated solution of aqueousNaHCO₃ for several times and finally extracted with CH₂Cl₂. The organiclayers were dried over MgSO₄ and the solvent was evaporated in vacuo.Flash chromatography of the residue on silica gel with a mixture ofhexane/ethyl acetate 40/1 gave the productN-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide.

Yield: 69 mg of a yellow oil (74%).

MS (EIMS): m/z 343 (M)⁺. IR (NaCl) ν (cm⁻¹): 3386, 2924, 2881, 1639,1458, 1254, 1068. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.90 (t, J=7.5 Hz, 3H), 1.55-1.87 (m, 3 H), 1.87-1.96 (m, 1 H), 2.62 (m, 1 H), 2.74-3.03 (m,3 H), 3.23 (m, 2 H), 3.79 (s, 3 H), 3.83-4.02 (m, 2 H), 4.08 (m, 1H),6.61-6.73 (m, 2 H), 6.85-6.98 (m, 2 H), 7.08 (dd, J=7.9 Hz, 5.1 Hz, 1H), 7.18 (dd, J=5.1 Hz, 1.0 Hz, 1 H). ¹³C NMR (CDCl₃, 150 MHz) δ (ppm):11.4, 11.6, 22.6, 24.8, 26.7, 27.3, 28.1, 28.2, 29.8, 29.8, 35.6, 35.9,44.1, 46.6, 51.8, 54.8, 55.2, 106.9, 107.0, 120.8, 120.8, 123.5, 124.2,124.6, 124.7, 125.8, 125.8, 126.3, 126.6, 126.7, 136.4, 136.9, 137.2,137.2, 157.3, 157.4, 169.5, 169.9.

(R)-N-(8-Methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide((R)-A4-1: R=OMe, Cy=2-thienyl)

Synthesis worked according to the preparation of A4-1 when using 39 mg(0.18 mmol) enantiomerical pure(R)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe) and 0.05mL (0.41 mmol) 2-thienyl acetic acid chloride. Flash chromatography wasdone with hexane/ethyl acetate 20/1.

Yield: 50 mg of a yellow oil (81%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A4-1.

[α]_(D) ²⁷=+70.6° (in MeOH).

(S)-N-(8-Methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide((S)-A4-1: R=OMe, Cy=2-thienyl)

Synthesis worked according to the preparation of A4-1 when using 310 mg(1.4 mmol) enantiomerical pure(S)-N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R=OMe) and 0.35mL (2.8 mmol) 2-thienyl acetic acid chloride. Flash chromatography wasdone with hexane/ethyl acetate 20/1.

Yield: 340 mg of a yellow oil (70%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A4-1.

[α]_(D) ²²=−25.6° (in MeOH).

N-(8-Methoxytetralin-2-yl)-N-propyl-2-phenylacetamide (A4-2: R=OMe,Cy=phenyl)

Synthesis worked according to the preparation of A4-1 when using 120 mg(0.55 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and0.11 mL (0.83 mmol) phenylacetic acid chloride (A3-2: W=Cl, Cy=phenyl).Flash chromatography was done with hexane/ethyl acetate 10/1.

Yield: 140 mg of colorless oil (78%).

MS (EIMS): m/z 337 (M)⁺. IR (NaCl) ν (cm⁻¹): 3356, 2962, 2931, 1639,1585, 1466, 1254, 1115. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.85-0.94 (m, 3H), 1.54-1.82 (m, 3 H), 1.92 (m, 1 H), 2.54-2.70 (m, 1 H), 2.73-3.02 (m,3 H), 3.19 (m, 2 H), 3.74 (s, 2 H), 3.79 (s, 3 H), 3.96-4.69 (m, 1 H),6.67 (m, 2 H), 7.09 (dd, J=7.8 Hz, 7.7 Hz, 1 H), 7.19-7.37 (m, 5 H). ¹³CNMR (CDCl₃, 90 MHz) δ (ppm): 11.5, 11.7, 22.7, 24.8, 26.9, 27.5, 28.0,28.1, 29.9, 31.9, 41.4, 42.0, 44.0, 46.6, 51.7, 54.6, 55.2, 106.9,107.0, 120.8, 120.8, 123.7, 124.4, 126.2, 126.6, 126.6, 126.7, 128.5,128.6, 128.8, 135.7, 136.5, 137.0, 157.4, 157.4, 170.6, 171.0.

CHN (%): C₂₂H₂₇NO₂ calculated (×0.1H₂O): C, 77.89; H 8.08; N, 4.13;found: C, 77.75; H, 7.82; N, 4.26.

N-(8-Methoxytetralin-2-yl)-N-propyl-2-(4-methoxyphenyl)acetamide (A4-3:R=OMe, Cy=4-methoxyphenyl)

Synthesis worked according to the preparation of A4-1 when using 110 mg(0.52 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and0.12 mL (0.79 mmol) 4-methoxyphenylacetic acid chloride (A3-3: W=Cl,Cy=4-methoxyphenyl). Flash chromatography was done with hexane/ethylacetate 10/1.

Yield: 160 mg of colorless oil (88%).

MS (EIMS): m/z 367 (M)⁺. IR (NaCl) ν (cm⁻¹): 3394, 2931, 2839, 1635,1466, 1250, 1068. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.81-0.95 (m, 3 H),1.53-1.83 (m, 3 H), 1.86-1.96 (m, 1 H), 2.53-3.01 (m, 4 H) 3.19 (m, 2H), 3.66 (s, 2 H), 3.78 (s, 3 H), 3.80 (s, 3 H), 4.02 (m, 1 H),6.61-6.72 (m, 2 H), 6.80-6.90 (m, 2 H) 7.04-7.24 (m, 3 H). ¹³C NMR(CDCl₃, 90 MHz) δ (ppm): 11.5, 11.7, 22.7, 24.8, 26.8, 27.5, 28.0, 28.1,29.7, 29.9, 40.5, 41.0, 43.9, 46.5, 51.7, 53.4, 54.5, 55.2, 55.3, 106.9,107.0, 114.1, 120.8, 120.9, 123.7, 124.4, 126.2, 126.6, 127.7, 129.5,129.8, 136.5, 137.0, 157.3, 157.4, 158.4, 158.4, 170.9, 171.3.

CHN (%): C₂₃H₂₉NO₃; calculated (×0.3 H₂O): C, 74.08; H, 8.00; N, 3.76;found: C, 74.20; H, 8.40; N, 3.65.

N-(8-Methoxytetralin-2-yl)-N-propyl-2-(2,5-dimethylphenyl)acetamide(A4-4: R=OMe, Cy=2,5-dimethylphenyl)

A mixture of 340 mg (2.1 mmol) 2,5-dimethylphenylacetic acid (A3-4:W=OH, Cy=2,5-dimethylphenyl) and 0.70 mL diisopropylethylamine (DIPEA)(4.24 mmol) in 10 mL of dry DMF was cooled in an ice-bath. Afteraddition of 950 mg (2.5 mmol)O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) in 5.0 mL dry DMF a solution of 640 mg (2.9mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine(A2-1) in 8.0 mL dry DMF was added dropwise, the ice-bath was removedand the reaction mixture was stirred for 3 hrs at room temperature. Themixture was washed with a saturated solution of aqueous NaHCO₃ forseveral times and the resulting aqueous layer was extracted with CH₂Cl₂.The organic layers were dried over MgSO₄ and the solvent was evaporatedin vacuo. Flash chromatography of the residue on silica gel with amixture of hexane/ethyl acetate 60/10 gave the productN-(8-methoxytetralin-2-yl)-N-propyl-2-(2,5-dimethylphenyl)acetamide.

Yield: 660 mg of a light-yellow solid (88%).

MP: 96° C.

MS (EIMS): m/z 365 (M)⁺. IR (NaCl) ν (cm⁻¹): 3386, 2927, 2866, 1643,1466, 1254, 1068. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.90 (t, J=7.4 Hz, 3H), 1.61-1.99 (m, 4 H), 2.19 (s, 3 H), 2.26 (s, 3 H), 2.58-3.37 (m, 6H), 3.61-3.72 (m, 2 H), 3.80 (s, 3 H), 3.95 (m, 1 H), 6.62-6.72 (m, 2H), 6.91-7.13 (m, 4 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 11.5, 11.7,19.2, 19.3, 20.9, 20.9, 22.8, 24.8, 26.9, 27.5, 28.0, 28.3, 29.8, 29.9,38.9, 39.3, 44.0, 46.7, 51.8, 54.4, 55.2, 107.0, 107.0, 120.8, 120.8,123.7, 124.4, 126.2, 126.6, 127.4, 127.5, 129.6, 129.7, 130.1, 130.1,133.0, 133.2, 134.0, 134.0, 135.4, 135.5, 136.5, 137.0, 157.4, 157.4,170.7, 171.1.

CHN (%): C₂₄H₃₁NO₂; calculated: C, 78.87; H, 8.55; N, 3.83; found: C,78.82; H, 8.67; N, 3.85.

N-(8-Methoxytetralin-2-yl)-N-propyl-2-(2-biphenyl-4-yl)acetamide (A4-5:R=OMe, Cy=2-biphenyl-4-yl)

Synthesis worked according to the preparation of A4-4 when using 370 mg(1.7 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and250 mg (1.2 mmol) 2-biphenyl-4-acetic acid (A3-5: W=OH,Cy=2-biphenyl-4-yl). Flash chromatography of the residue on silica gelwith a mixture of hexane/ethyl acetate 20/1 gave the product.

Yield: 469 mg of a white solid (97%).

MP: 43° C.

MS (EIMS): m/z 413 (M)⁺. IR (NaCl) ν (cm⁻¹): 2962, 2933, 2837, 1635,1583, 1466, 1444, 1254, 1115, 1092, 756. ¹H NMR (CDCl₃, 360 MHz) δ(ppm): 0.85-0.97 (m, 3 H), 1.57-1.86 (m, 3 H), 1.94 (m, 1 H), 2.56-3.04(m, 4 H), 3.23 (m, 2 H), 3.76-3.82 (m, 5 H), 4.06 (m, 1 H), 6.63-6.72(m, 2 H), 7.09 (dd, J=7.8 Hz, 7.7 Hz, 1H), 7.29-7.46 (m, 5 H), 7.51-7.62(m, 4 H). ¹³C NMR (CDCl₃, 150 MHz) δ (ppm): 11.5, 11.7, 22.7, 24.9,26.9, 27.5, 28.0, 28.2, 29.8, 29.9, 41.0, 41.5, 44.0, 46.6, 51.8, 54.6,55.2, 107.0, 107.0, 120.8, 120.8, 123.6, 124.4, 126.2, 126.6, 127.0,127.1, 127.2, 127.2, 127.3, 127.4, 128.7, 129.0, 129.3, 134.7, 134.8,136.5, 137.0), 139.6, 139.6, 140.8, 141.0, 157.4, 157.4, 170.5, 170.9.

CHN (%): C₂₈H₃₁NO₂; calculated: C, 81.32; H, 7.56; N, 3.39; found: C,81.42; H 7.33; N, 3.43.

N-(8-Methoxytetralin-2-yl)-N-propyl-2-adamantylacetamide (A4-6: R=OMe,Cy=adamantyl)

Synthesis worked according to the preparation of A4-4 when using 570 mg(2.6 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and360 mg (1.9 mmol) 2-adamantylacetic acid (A3-6: W=OH, Cy=adamantyl).Flash chromatography of the residue on silica gel with a mixture ofhexane/ethyl acetate 10/1 gave the product.

Yield: 580 mg of colourless oil (78%).

MS (EIMS): m/z 395 (M)⁺. IR (NaCl) ν (cm⁻¹): 3421, 2900, 2846, 1631,1466, 1254, 1095, 756. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.85-0.94 (m, 3H), 1.51-1.76 (m, 15 H), 1.82-2.02 (m, 4 H), 2.04-2.31 (m, 2 H), 2.59(m, 1 H), 2.81-2.99 (m, 3 H), 3.19 (m, 2 H), 3.80 (s, 3 H), 4.10 (m, 1H), 6.62-6.77 (m, 2 H), 7.04-7.17 (m, 1 H). ¹³C NMR (CDCl₃, 150 MHz) δ(ppm): 11.5, 11.8, 23.2, 24.9, 27.1, 27.8, 28.2, 28.4, 28.8, 28.8, 29.9,29.9, 33.5, 33.8, 36.8, 36.9, 42.8, 42.9, 43.7, 46.5, 46.6, 46.7, 50.7,54.8, 55.3, 106.9, 107.0, 120.8, 120.8, 123.9, 124.5, 126.2, 126.6,136.6, 137.1, 157.4, 157.4, 170.7, 171.4.

CHN (%): C₂₆H₃₇NO₂; calculated: C, 78.94; H, 9.43; N, 3.54; found: C,78.77; H, 9.71; N, 3.36.

2c. Synthesis of Amines According to Formula A5

Compounds according to formula A4 were hydrogenized using reductiveagents like lithium aluminiumhydride in diethyl ether. The reaction wasterminated by adding an aqueous solution of sodium hydrogen carbonate,the mixture was purified over Celite™, the amine was extracted withorganic solvents and purified by flash chromatography to get derivativesof formula A5 which represent final compounds as embodiments of thisdisclosure

Compound 2:N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A5-1:R=OMe, Cy=2-thienyl)

To a solution of 16 mg (0.05 mmol) ofN-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide (A4-1: R=OMe,Cy=2-thienyl) in 10 mL dry diethyl ether 0.15 mL of a 1M solution ofLiAlH₄ (0.15 mmol) in dry diethyl ether were added dropwise and stirredfor 20 hrs at room temperature. The reaction was terminated by adding asaturated aqueous solution of sodium hydrogen carbonate, the solutionwas filtered through a matrix consisting of Celite™-MgSO₄-Celite™ andsubsequently washed with methylenehloride and ethyl acetate. Afterevaporating the organic solvents in vacuo the residue was purified byflash chromatography on silica gel with a mixture of hexane/ethylacetate 10/1 in the presence of 0.5% (v/v) dimethylethylamine to getcompound 2(N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A5-1:R=OMe, Cy=2-thienyl)).

Yield: 9.8 g of colorless oil (64%).

MS (EIMS): m/z 329 (M)⁺. IR (NaCl) ν (cm⁻¹): 3356, 2927, 1585, 1466,1435, 1254, 1072, 1022. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.90 (t, J=7.3Hz, 3 H), 1.50 (m, 2 H), 1.55-1.67 (m, 1 H), 1.99 (m, 1 H), 2.43 (dd,J=18.2 Hz, 12.2 Hz, 1 H), 2.57 (m, 2 H), 2.76-3.03 (m, 8 H), 3.81 (s, 3H), 6.65 (d, J=8.1 Hz, 1 H), 6.70 (m, 1 H), 6.81 (m, 1 H), 6.91 (dd,J=5.2 Hz, 3.4 Hz, 1 H), 7.07 (dd, J=7.9 Hz, 5.2 Hz, 1 H), 7.11 (dd,J=5.2 Hz, 1.2 Hz, 1 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 11.9, 22.5,25.5, 26.2, 30.2, 30.3, 52.8, 52.9, 55.2, 57.2, 106.8, 120.8, 123.1,124.4, 125.4, 126.0, 126.5, 137.9, 143.3, 157.6.

CHN (%): C₂₀H₂₇NOS; calculated: C, 72.90; H, 8.26; N, 4.25 S, 9.73;found: C, 72.69; H, 8.25; N, 4.13; S, 9.39.

Compound 2a:(R)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine((R)-A5-1: R=OMe, Cy=2-thienyl)

Synthesis worked according to the preparation of A5-1 when using 45 mg(0.13 mmol)(R)-N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide((R)-A4-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using amixture of hexane/ethyl acetate 40/1 in the presence of 0.5% (v/v)dimethylethylamine.

Yield: 25 mg of colorless oil (57%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A5-1.

[α]_(D) ²⁷=+59.8° (in MeOH).

Compound 2b:(S)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine((5)-A5-1: R=OMe, Cy=2-thienyl)

Synthesis worked according to the preparation of A5-1 when using 340 mg(0.99 mmol)(S)-N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-thienyl)acetamide((S)-A4-1: R=OMe, Cy=2-thienyl). Flash chromatography was done using amixture of hexane/ethyl acetate 40/1 in the presence of 0.5% (v/v)dimethylethylamine.

Yield: 73 mg of colorless oil (23%).

MS, IR, ¹H NMR and ¹³C NMR are identical with the data of compound A5-1.

[α]_(D) ²⁷=−56.3° (in MeOH).

Compound 4: N-(8-Methoxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine(A5-2: R=OMe, Cy=phenyl)

Synthesis worked according to the preparation of A5-1 when using 120 mg(0.37 mmol) N-(8-methoxytetralin-2-yl)-N-propyl-2-phenylacetamide (A4-2:R=OMe, Cy=phenyl). Flash chromatography was done using a mixture ofhexane/ethyl acetate 20/1 in the presence of 0.5% (v/v)dimethylethylamine.

Yield: 88 mg of a light yellow oil (74%).

MS (EIMS): m/z 323 (M)⁺. IR (NaCl) ν (cm⁻¹): 3381, 2933, 1468, 1255,1070, 769. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.90 (t, J=7.4 Hz, 3 H, 1.51(m, 2 H), 1.56-1.67 (m, 1 H), 1.98 (m, 1 H), 2.43 (m, 1 H), 2.57 (m, 2H), 2.72-3.04 (m, 8 H), 3.81 (s, 1 H), 6.65 (d, J=8.1 Hz, 1 H), 6.69 (d,J=7.6 Hz, 1 H), 7.07 (dd, J=8.1 Hz, 7.6 Hz, 1 H), 7.14-7.30 (m, 5 H).¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 11.9, 22.4, 25.5, 26.2, 30.2, 36.2,52.8, 53.1, 55.2, 57.1, 106.8, 120.8, 125.4, 125.8, 125.9, 128.2, 128.8,137.9, 141.0, 157.6.

CHN (%): C₂₂H₂₉NO; calculated (×0.2 H₂O): C, 80.79; H, 9.06; N, 4.28;found: C, 80.69; H, 9.17; N, 4.24.

Compound 6:N-[2-(4-Methoxyphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-3: R=OMe, Cy=4-methoxyphenyl)

Synthesis worked according to the preparation of A5-1 when using 140 mg(0.39 mmol)N-(8-methoxytetralin-2-yl)-N-propyl-2-(4-methoxyphenyl)acetamide (A4-3:R=OMe, Cy=4-methoxyphenyl). Flash chromatography was done using amixture of hexane/ethyl acetate 20/1 in the presence of 0.5% (v/v)dimethylethylamine.

Yield: 110 mg of a light yellow oil (77%).

MS (EIMS): m/z 353 (M)⁺. IR (NaCl) ν (cm⁻¹): 3392, 2935, 1468, 1252,1034, 771. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.90 (t, J=7.4 Hz, 3 H),1.50 (m, 2 H, 1.55-1.67 (m, 1 H, 1.98 (m, 1 H, 2.42 (dd, J=18.2 Hz, 12.6Hz, 1 H), 2.57 (m, 2 H), 2.67-3.03 (m, 8 H), 3.78 (s, 3 H), 3.81 (s, 3H), 6.65 (d, J=8.1 Hz, 1 H), 6.69 (d, J=7.7 Hz, 1 H), 6.82 (m, 2 H),7.07 (dd, J=8.1 Hz, 7.7 Hz, 1 H), 7.12 (m, 2 H). ¹³C NMR (CDCl₃, 150MHz) δ (ppm): 11.9, 22.4, 25.5, 26.2, 30.2, 35.3, 52.8, 53.3, 55.2,55.2, 57.1, 106.8, 113.7, 120.8, 125.4, 125.9, 129.7, 133.1, 137.9,157.6, 157.8.

CHN (%): C₂₃H₃₁NO₂; calculated (×0.125 H₂O): C, 77.65; H, 8.85; N, 3.94;found: C, 77.55; H, 9.03; N, 3.89.

Compound 8:N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2,5-dimethyl)phenylethyl]amine(A5-4: R=OMe, Cy=2,5 dimethylphenyl)

Synthesis worked according to the preparation of A5-1 when using 510 mg(1.4 mmol)N-(8-methoxytetralin-2-yl)-N-propyl-2-(2,5-dimethyl)phenylacetamide(A4-4: R=OMe, Cy=2,5-dimethylphenyl). Flash chromatography was doneusing a mixture of hexane/ethyl acetate 20/1 in the presence of 0.5%(v/v) dimethylethylamine.

Yield: 350 mg of a yellow oil (72%).

MS (EIMS): m/z 351 (M)⁺. IR (NaCl) ν (cm⁻¹): 3417, 2931, 1647, 1466,1254, 1068. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.92 (t, J=7.4 Hz, 3 H),1.48-1.68 (m, 3 H), 2.02 (m, 1 H), 2.29 (s, 6 H), 2.44 (dd, J=18.2 Hz,12.2 Hz, 1 H), 2.60 (m, 2 H), 2.67-3.06 (m, 8 H), 3.81 (s, 3 H), 6.65(d, J=8.1 Hz, 1 H), 6.70 (m, 1 H), 6.90 (dd, J=7.6 Hz, 1.9 Hz, 1 H),6.96 (d, J=1.9 Hz, 1 H), 7.01 (d, J=7.6 Hz, 1 H), 7.07 (dd, J=8.1 Hz,7.7 Hz, 1 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 11.9, 18.9, 20.9, 22.2,25.6, 26.2, 30.2, 33.5, 51.7, 52.9, 55.2, 57.3, 106.9, 120.8, 125.3,126.0, 126.7, 130.1, 130.2, 132.8, 135.3, 137.8, 138.7, 157.6.

CHN (%): C₂₄H₃₃NO; calculated (×0.2 H₂O): C, 81.17; H, 9.48; N, 3.94;found: C, 81.30; H, 9.48; N, 3.94.

Compound 10:N-(2-Adamantylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine (A5-5:R=OMe, Cy=adamantyl)

Synthesis worked according to the preparation of A5-1 when using 560 mg(1.4 mmol) N-(8-methoxytetralin-2-yl)-N-propyl-2-adamantylacetamide(A4-5: R=OMe, Cy=adamantyl). Flash chromatography was done using amixture of hexane/ethyl acetate 30/1 in the presence of 0.5% (v/v)dimethylethylamine.

Yield: 340 mg of a light yellow oil (63%).

MS (EIMS): m/z 381 (M)⁺. IR (NaCl) ν (cm⁻¹): 3379, 2900, 2843, 1585,1466, 1254, 1072. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.89 (t, J=7.4 Hz, 3H), 1.27 (m, 2 H), 1.42-1.74 (m, 15 H), 1.88-2.02 (m, 4 H), 2.36-2.99(m, 9 H), 3.82 (s, 3 H), 6.65 (d, J=8.0 Hz, 1 H), 6.70 (m, 1 H), 7.07(dd, J=8.0 Hz, 7.8 Hz, 1 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 12.0,22.2, 25.3, 26.2, 28.8, 30.2, 32.1, 37.3, 42.6, 44.5, 52.9, 55.3, 54.1,106.9, 120.8, 125.4, 126.0, 137.9, 157.6.

CHN (%): C₂₆H₃₉NO; calculated (×0.4 H₂O): C, 80.32; H, 10.32; N, 3.60;found: C, 80.18; H, 10.28; N, 3.59.

N-[2-(2-Biphenyl-4-yl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-6: R=OMe, Cy=2-biphenyl-4-yl)

Synthesis worked according to the preparation of A5-1 when using 470 mg(1.1 mmol)N-(8-methoxytetralin-2-yl)-N-propyl-2-(2-biphenyl-4-yl)acetamide (A4-5:R=OMe, Cy=2-biphenyl-4-yl) and THF as the solvent. Flash chromatographywas done using hexane in the presence of 0.5% (v/v) dimethylethylamine.

Yield: 210 mg of a light yellow oil (47%).

MS (EIMS): m/z 399 (M)⁺. IR (NaCl) ν (cm⁻¹): 3417, 3006, 2930, 2870,2835, 1585, 1468, 1438, 1339, 1252, 1097, 1072, 1008, 763, 697. ¹H NMR(CDCl₃, 360 MHz) δ (ppm): 0.91 (t, J=7.4 Hz, 3 H), 1.47-1.68 (m, 3 H),2.00 (m, 1 H), 2.44 (m, 1 H), 2.59 (m, 2 H), 2.76-3.05 (m, 8 H), 3.81(s, 3 H), 6.65 (d, J=8.1 Hz, 1 H), 6.70 (d, J=7.6 Hz, 1 H), 7.07 (dd,J=8.1 Hz, 7.6 Hz, 1 H), 7.26-7.34 (m, 3 H), 7.42 (m, 2 H), 7.48-7.61 (m,4 H). ¹³C NMR (CD₃OD, 90 MHz) δ (ppm): 11.9, 22.4, 25.6, 26.2, 30.2,35.9, 52.8, 53.0, 55.2, 57.2, 106.8, 120.8, 125.4, 126.0, 126.9, 127.0,128.7, 129.2, 137.9, 138.8, 140.1, 141.2, 157.6.

CHN (%): C₂₈H₃₃NO; calculated: C, 84.17; H, 8.32; N, 3.51; found: C,84.31; H, 8.29; N, 3.66.

Compound 12:N-(2-Ferrocenylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine (A5-7:R=OMe, Cy=ferrocenyl)

Synthesis worked according to the preparation of A4-4 when using 360 mg(1.6 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and240 mg (0.99 mmol) ferrocenylacetic acid (A3-7: W=OH, Cy=ferrocenyl).Flash chromatography of the residue on silica gel with a mixture ofhexane/ethyl acetate 10/1 gave the crude productN-(8-methoxytetralin-2-yl)-N-propyl-2-ferrocenylacetamide.

Because of its instability the residue was immediately reacted to getcompound 12(N-(2-ferrocenylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine (A5-7:R=OMe, Cy=ferrocenyl)). This reaction was achieved according to thepreparation of A5-1 when using 98 mg of crudeN-(8-methoxytetralin-2-yl)-N-propyl-2-ferrocenylacetamide dissolved in amixture of 5.0 mL diethyl ether and 3.0 mL THF. Flash chromatography wasdone using a mixture of hexane/ethyl acetate 40/1 in the presence of0.5% (v/v) dimethylethylamine to yield compound 12.

Yield: 25 mg of a yellow oil (6%).

MS (EIMS): m/z 431 (M)⁺. IR (NaCl) ν (cm⁻¹): 3774, 3329, 2819, 1815,1664, 1589, 1406, 1203, 1057, 1026, 783. ¹H NMR (CDCl₃, 360 MHz) δ(ppm): 0.91 (t, J=7.4 Hz, 3 H), 1.51 (m, 2 H), 1.62 (m, 1 H), 1.99 (m, 1H), 2.38-2.58 (m, 5 H), 2.69-3.02 (m, 6 H), 3.81 (s, 3 H), 4.02-4.12 (m,9 H), 6.65 (m, 1 H), 6.70 (m, 1 H), 7.07 (dd, J=8.0 Hz, 7.7 Hz, 1 H).¹³C NMR (CDCl₃, 150 MHz) δ (ppm): 12.0, 22.4, 25.6, 26.2, 29.5, 30.2,52.1, 52.8, 55.2, 57.0, 67.1, 67.1, 68.1, 68.4, 87.2, 106.8, 120.8,125.4, 126.0, 137.9, 157.6.

HR-MS: C₂₆H₃₃FeNO; calculated: 431.1912; found: 431.1912.

Compound 14:N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-([2.2]paracyclophan-4-yl)ethyl]amine(A5-8: R=OMe, Cy=[2.2]paracyclophan-4-yl)

Synthesis worked according to the preparation of A4-4 when using 160 mg(0.75 mmol) N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and110 mg (0.42 mmol) [2.2]paracyclophan-4-ylacetic acid (A3-8: W=OH,Cy=[2.2]paracyclophan-4-yl). Flash chromatography of the residue onsilica gel with a mixture of hexane/ethyl acetate 40/10 gave the crudeproductN-(8-methoxytetralin-2-yl)-N-propyl-2-([2.2]paracyclophan-4-yl)acetamide.The residue was dissolved in 5.0 mL diethyl ether and reacted asdescribed for the preparation of A5-1. Flash chromatography was doneusing a mixture of hexane/ethyl acetate 20/1 in the presence of 0.5%(v/v) dimethylethylamine to yield compound 14.

Yield: 58 mg of a light yellow oil (31%).

MS (EIMS): m/z 453 (M)⁺. IR (NaCl) ν (cm⁻¹): 3418, 2929, 2853, 1666,1586, 1469, 1438, 1254, 1096, 1070, 796, 767, 716. ¹H NMR (CDCl₃, 360MHz) δ (ppm): 0.93 (m, 3 H), 1.48-1.68 (m, 3 H, Pr-2), 2.00 (m, 1 H),2.34-3.17 (m, 18 H), 3.37 (m, 1 H), 3.81 (s, 3 H), 6.14 (m, 1 H),6.36-6.54 (m, 5 H), 6.63-6.73 (m, 3 H), 7.08 (dd, J=8.1 Hu, 7.8 Hz, 1H). ¹³C NMR (CDCl₃, 150 MHz) δ (ppm): 12.0, 22.4, 25.6, 25.8, 26.1,26.2, 30.1, 30.2, 30.2, 33.6, 34.3, 35.0, 35.3, 51.9, 52.0, 53.0, 53.1,55.2, 57.3, 57.3, 106.8, 120.7, 120.8, 125.4, 126.0, 129.1, 130.4,132.1, 133.1, 133.3, 134.6, 134.7, 135.0, 135.1, 137.5, 137.6, 137.9,139.3, 139.4, 139.6, 139.7, 140.0, 140.1, 157.6.

2d. Synthesis of Amines According to Formula A7

Compounds according to formula I carrying a hydroxyl group at position 8(R=OH) and being identical to the general structure as described informula A7 were synthesized starting from compounds according to formulaA6 (R1=(C1-C3)alkyl), which have already been synthesized as embodimentsof this disclosure. Acid supported hydrolysis of the methoxy group ofcompounds according to formula A6 (R1=Me) was achieved by utilizingborotribromide (Horn Pharmaceutisch Weekblad Sci. Ed. 1985, Vol 7, p208) as a Lewis acid in methylenehloride to afford the 8-OH substitutedfinal compounds according to formula A7 as embodiments of thisdisclosure.

Compound 1:N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A7-1:R=OMe, Cy=2-thienyl)

A solution of 6.5 g (20 mmol) ofN-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A5-1:R=OMe, Cy=2-thienyl) in 40 mL dry methylenchloride was added to asolution of 80 mL of a 1M solution of BBr₃ in methylenehloride (80 mmol)and was stirred for 3 hrs at room temperature. The reaction solution wasadded to a mixture of 5.0 mL 25% aqueous NH₃ and 15 g ice and furtherstirred for 45 min. The organic and the aqueous phase were separated andthe last one was extracted with methylenehloride for several times. Allorganic phases were collected, washes with saturated aqueous solutionsof sodium hydrogen carbonate and sodium chloride, respectively and driedover MgSO₄. The solvent was evaporated in vacuo and the residue waspurified by flash chromatography using a mixture of hexane/ethyl acetate10/1 in the presence of 1% (v/v) of dimethylethylamine.

Yield: 1.1 g of a light brown solid (17%).

MP: 99° C.

MS (EIMS): m/z 315 (M)⁺. IR (NaCl) ν (cm⁻¹): 3367, 2931, 2870, 1585,1462, 1261, 1080. ¹H NMR (CDCl₃, 600 MHz) δ (ppm): 0.91 (t, J=7.4 Hz, 3H, —CH₂—CH₂—CH ₃), 1.46-1.66 (m, 3 H, —CH₂—CH ₂—CH₃, axial H-3′), 2.01(m, 1 H, equatorial H-3′), 2.42 (dd, J=16.3 Hz, 11.2 Hz, 1 H, axialH-1′), 2.58 (m, 2 H, —CH ₂—CH₂—CH₃), 2.75-3.07 (m, 8 H, equatorial H-1′,H-2′, axial H-4′, equatorial H-4′, N—CH₂—CH ₂-thienyl, N—CH₂—CH₂-thienyl), 6.60 (m, 1 H, H-7′), 6.68 (m, 1 H, H-5′), 6.82 (m, 1 H,H-3), 6.92 (dd, J=5.2 Hz, 3.4 Hz, 1 H, H-4), 6.98 (m, 1 H, H-6′), 7.12(dd, J=5.2 Hz, 1.2 Hz, 1 H, H-5). ¹³C NMR (CD₃OD, 150 MHz) δ (ppm): 11.9(—CH₂—CH₂—CH₃), 22.4 (—CH₂—CH₂—CH₃), 25.5 (C-1′ or C-3′), 25.6 (C-3′ orC-1′), 30.2 (C-4′ or N—CH₂—CH₂-thienyl), 30.3 (N—CH₂—CH₂-thienyl orC-4′), 52.7 (—CH₂—CH₂—CH₃ or N—CH₂—CH₂-thienyl), 52.9 (N—CH₂-CH₂-thienylor —CH₂—CH₂—CH₃), 57.2 (C-2′), 111.9 (C-7′), 121.0 (C-5′), 122.9(C-8a′), 123.2 (C-5), 124.6 (C-3), 126.3 (C-6′), 126.6 (C-4), 138.2(C-4-a′), 143.3 (C-2), 153.7 (C-8′).

CHN (%): C₁₉H₂₅NOS; calculated (×0.125 H₂O): C, 71.83; H, 8.01; N, 4.41;S, 10.09; found: C, 71.90; H, 8.25; N, 4.32; S, 10.11.

Compound 1a:(R)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine((R)-A7-1: Cy=2-thienyl)

Synthesis worked according to the preparation of A7-1 when using 21 mg(0.06 mmol)(R)-N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine((R)-A5-1: R=OMe, Cy=2-thienyl). Flash chromatography was done usinghexane/ethyl acetate 40/10 in the presence of 0.5% (v/v)dimethylethylamine to achieve compound 1a.

Yield: 14 mg of a light yellow oil (70%).

MS, ¹H NMR and ¹³C NMR are identical with the data of compound A7-1.

[α]_(D) ²⁷=+47.6° (in MeOH).

Compound 1b:(S)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine((S)-A7-1: Cy=2-thienyl)

Synthesis worked according to the preparation of A7-1 when using 76 mg(0.23 mmol)(S)-N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine((S)-A5-1: R=OMe, Cy=2-thienyl). Flash chromatography was done usinghexane/ethyl acetate 10/1 in the presence of 1% (v/v) ofdimethylethylamine to achieve compound 1b.

Yield: 39 mg of colorless oil (52%).

MS, ¹H NMR and ¹³C NMR are identical with the data of compound A7-1.

[α]_(D) ²²=−38.2° (in MeOH).

Compound 3: N-(8-Hydroxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine(A7-2: Cy=phenyl)

Synthesis worked according to the preparation of A7-1 when using 58 mg(0.18 mmol) N-(8-methoxytetralin-2-yl)-N-(2-phenylethyl)-N-propylamine(A5-2: R=OMe, Cy=phenyl). Flash chromatography was done usinghexane/ethyl acetate 40/10 in the presence of 0.5% (v/v)dimethylethylamine to achieve compound 3.

Yield: 32 mg of a yellow oil (57%).

MS (EIMS): m/z 309 (M)⁺. IR (NaCl) ν (cm⁻¹): 3386, 2931, 2870, 1585,1462, 1331, 1269, 1084, 876. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 0.91 (t,J=7.4 Hz, 3 H), 1.46-1.65 (m, 3 H), 2.00 (m, 1 H), 2.39 (dd, J=16.2 Hz,11.2 Hz, 1 H), 2.59 (m, 2 H.), 2.72-3.07 (m, 8 H), 6.60 (d, J=7.9 Hz, 1H), 6.67 (d, J=7.5 Hz, 1 H), 6.98 (dd, J=7.9 Hz, 7.5 Hz, 1 H), 7.16-7.31(m, 5 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 11.9, 22.3, 25.6, 30.2, 36.2,52.8, 52.9, 57.1, 111.9, 120.9, 122.9, 125.9, 126.3, 128.2 128.9, 138.3,140.9, 153.7.

CHN (%): C₂₁H₂₇NO; calculated (×0.1H₂O): C, 81.04; H, 8.81; N, 4.50;found: C, 81.36; H, 9.26; N, 4.11.

Compound 5:N-(8-Hydroxytetralin-2-yl)-N-[2-(4-methoxyphenyl)ethyl]-N-propylamine(A7-3: Cy=4-methoxyphenyl)

Synthesis worked according to the preparation of A7-1 when using 80 mg(0.23 mmol)N-(8-methoxytetralin-2-yl)-N-[2-(4-methoxyphenyl)ethyl]-N-propylamine(A5-3: R=OMe, Cy=4-methoxyphenyl). Flash chromatography was done usinghexane/ethyl acetate 30/20 in the presence of 0.5% (v/v)dimethylethylamine to achieve compound 5.

Yield: 46 mg light yellow oil (60%).

MS (EIMS): m/z 325 (M)⁺. IR (NaCl) ν (cm⁻¹): 3394, 2920, 2862, 1639,1439, 1045, 663. ¹H NMR (CD₃OD, 360 MHz) δ (ppm): 0.94 (t, J=7.4 Hz, 3H), 1.51-1.64 (m, 3 H), 2.05 (m, 1 H), 2.45 (dd, J=17.7 Hz, 12.6 Hz, 1H), 2.60-3.06 (m, 10 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 6.70 (m, 2 H),6.88 (dd, J=8.0 Hz, 7.7 Hz, 1 H), 7.03 (m, 2 H). ¹³C NMR (CD₃OD, 90 MHz)δ (ppm): 12.2, 22.5, 26.9, 27.0, 30.9, 35.0, 53.9, 54.4, 58.9, 112.6,116.2, 120.7, 124.0, 127.1, 130.6, 132.5, 138.8, 156.3, 156.7.

Compound 7:N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine(A7-4: Cy=2,5-dimethylphenyl)

Synthesis worked according to the preparation of A7-1 when using 63 mg(0.18 mmol)N-[2-(2,5-dimethylphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-4: R=OMe, Cy=2,5-dimethylphenyl). Flash chromatography was doneusing hexane/ethyl acetate 40/10 in the presence of 0.5% (v/v)dimethylethylamine to achieve compound 7.

Yield: 47 mg of a white solid (79%).

MP: 102° C.

MS (EIMS): m/z 337 (M)⁺. IR (NaCl) ν (cm⁻¹): 3383, 2931, 2873, 1647,1585, 1462, 1041. ¹H NMR (CDCl₃, 600 MHz) δ (ppm): 0.93 (t, J=7.3 Hz, 3H), 1.52-1.65 (m, 3 H), 2.04 (m, 1 H), 2.29 (s, 6 H), 2.42 (dd, J=16.1Hz, 11.3 Hz, 1 H), 2.61 (m, 2 H.), 2.69-2.92 (m, 7 H), 3.05 (m, 1 H),6.60 (d, J=7.8 Hz, 1 H), 6.68 (d, J=7.6 Hz, 1 H), 6.92 (dd, J=7.8 Hz,1.8 Hz, 1 H), 6.96 (d, J=1.8 Hz, 1 H), 6.99 (d, J=7.8 Hz, 1 H), 7.02(dd, J=7.8 Hz, 7.6 Hz, 1 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 12.0,18.9, 20.9, 22.3, 25.7, 25.7, 30.2, 33.7, 51.6, 53.0, 57.2, 111.9,120.9, 122.9, 126.3, 126.7, 130.1, 130.3, 132.8, 135.3, 137.3, 138.7,153.7.

CHN (%): C₂₃H₃₁NO; calculated (×0.2 H₂O): C, 80.99; H, 9.28; N, 4.11;found: C, 80.97; H, 8.33; N, 4.05.

Compound 9:N-(2-Adamantylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine (A7-5:Cy=adamantyl)

Synthesis worked according to the preparation of A7-1 when using 78 mg(0.20 mmol)N-(2-adamantylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine (A5-5:R=OMe, Cy=adamantyl). Flash chromatography was done using hexane/ethylacetate 40/10 in the presence of 0.5% (v/v) dimethylethylamine toachieve compound 9.

Yield: 56 mg of a colorless oil (74%).

MS (EIMS): m/z 367 (M)⁺. IR (NaCl) ν (cm⁻¹): 3394, 2900, 2846, 1643,1585, 1462, 1045. ¹H NMR (CDCl₃, 600 MHz) δ (ppm): 0.89 (t, J=7.4 Hz, 3H), 1.27 (m, 2 H), 1.46-1.54 (m, 8 H), 1.56-1.72 (m, 7 H), 1.93 (m, 3H), 2.01 (m, 1 H), 2.44-2.52 (m, 3 H), 2.57 (m, 2 H), 2.78-2.91 (m, 3H), 3.00 (m, 1 H), 6.60 (d, J=7.9 Hz, 1 H), 6.65 (d, J=7.7 Hz, 1 H),6.98 (dd, J=7.9 Hz, 7.7 Hz, 1 H). ¹³C NMR (CDCl₃, 150 MHz) δ (ppm):12.0, 22.3, 25.4, 25.8, 28.7, 30.2, 32.0, 37.2, 42.6, 44.5, 52.8, 57.0,111.9, 120.9, 123.1, 126.2, 138.4, 153.8.

CHN (%): C₂₅H₃₇NO; calculated: C, 81.69; H, 10.15; N, 3.81; found: C,81.62; H, 10.55; N, 3.35.

N-[2-(2-Biphenyl-4-yl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine(A7-6: Cy=2-biphenyl-4-yl)

Synthesis worked according to the preparation of A7-1 when using 120 mg(0.29 mmol)N-[2-(2-biphenyl-4-yl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-6: R=OMe, Cy=2-biphenyl-4-yl). Flash chromatography was done usinghexane/ethyl acetate 40/10 in the presence of 1% (v/v)dimethylethylamine to achieve compound A7-6.

Yield: 39 mg of a white solid (35%).

MP: 52° C.

MS (EIMS): m/z 385 (M)⁺. IR (NaCl) ν (cm⁻¹): 3388, 2957, 2931, 2870,1585, 1486, 1464, 1331, 1266, 1085, 825, 763, 732, 697. ¹H NMR (CDCl₃,360 MHz) δ (ppm): 0.92 (t, J=7.4 Hz, 3 H), 1.47-1.68 (m, 3 H), 2.02 (m,1 H), 2.45 (dd, J=16.1 Hz, 11.1 Hz, 1 H), 2.60 (m, 2 H), 2.75-2.93 (m, 7H), 3.05 (m, 1 H), 6.59 (d, J=7.7 Hz, 1 H), 6.68 (d, J=7.5 Hz, 1 H),6.98 (dd, J=7.7 Hz, 7.5 Hz, 1 H), 7.25-7.35 (m, 3 H), 7.42 (m, 2 H),7.51 (m, 2 H), 7.57 (m, 2 H). ¹³C NMR (CDCl₃, 90 MHz) δ (ppm): 11.9,22.3, 25.6, 25.8, 30.2, 35.8, 52.9, 52.9, 57.1, 111.9, 120.9, 123.0,126.2, 127.0, 128.7, 129.3, 138.3, 138.9, 140.0, 141.1, 153.7.

Compound 11:N-(2-Ferrocenylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine (A7-7:Cy=ferrocenyl)

Synthesis worked according to the preparation of A7-1 when using 73 mg(0.17 mmol)N-(2-ferrocenylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine (A5-7:R=OMe, Cy=ferrocenyl). Flash chromatography was done using hexane/ethylacetate 30/20 in the presence of 0.5% (v/v) dimethylethylamine toachieve compound 11.

Yield: 31 mg of a red brown oil (43%).

MS (EIMS): m/z 417 (M)⁺. IR (NaCl) ν (cm⁻¹): 3398, 2927, 2854, 1589,1462, 1435, 1053. ¹H NMR (CDCl₃/CD₃OD, 360 MHz) δ (ppm): 0.95 (t, J=7.4Hz, 3 H), 1.49-1.70 (m, 3 H), 2.07 (m, 1 H), 2.44-2.58 (m, 3 H), 2.61(m, 2 H), 2.75-3.08 (m, 6 H), 4.01-4.10 (m, 4 H), 4.12 (s, 5 H), 6.61(m, 1 H), 6.63 (m, 1 H), 6.95 (dd, J=7.9 Hz, 7.7 Hz, 1 H). ¹³C NMR(CDCl₃, 90 MHz) δ (ppm): 11.2, 20.9, 24.8, 25.6, 27.7, 29.5, 51.4, 52.4,56.9, 66.7, 67.5, 67.9, 86.1, 111.0, 119.2, 122.5, 125.6, 137.2, 154.5.

CHN (%): C₂₅H₃₁FeNO; calculated (×0.5 H₂O): C, 70.42; H, 7.56; N, 3.29;found: C, 70.35; H, 7.50; N, 3.36.

Compound 13:N-(8-Hydroxytetralin-2-yl)-N-[2-([2.2]paracyclophan-4-yl)ethyl]-N-propylamine(A7-8: Cy=[2.2]paracyclophan-4-yl)

Synthesis worked according to the preparation of A7-1 when using 34 mg(0.07 mmol)N-(8-methoxytetralin-2-yl)-N-[2-([2.2]paracyclophan-4-yl)ethyl]-N-propylamine(A5-8: R=OMe, Cy=[2.2]paracyclophan-4-yl). Flash chromatography was doneusing hexane/ethyl acetate 40/10 in the presence of 1% (v/v)dimethylethylamine to achieve compound 13.

Yield: 22 mg of colorless oil (65%).

MS (EIMS): m/z 440 (M)⁺. IR (NaCl) ν (cm⁻¹): 3359, 3033, 2929, 2852,1586, 1464, 1436, 1331, 1265, 1085, 768, 737, 716. ¹H NMR (CDCl₃, 360MHz) δ (ppm): 0.94 (t, J=7.3 Hz, 3 H), 1.49-1.64 (m, 3 H), 2.01 (m, 1H), 2.31-3.16 (m, 18 H), 3.36 (m, 2 H), 6.13 (m, 1 H), 6.37-6.52 (m, 5H), 6.59 (d, J=7.9 Hz, 1 H), 6.64-6.69 (m, 2 H), 6.98 (t, J=8.0 Hz, 7.7Hz, 1 H). ¹³C NMR (CDCl₃, 150 MHz) δ (ppm): 12.0, 22.2, 25.5, 25.5,25.6, 25.7, 30.1 30.2, 33.6, 33.7, 34.3, 35.0, 35.3, 51.8, 51.9, 53.1,53.2, 57.2, 57.3, 111.9, 120.7, 120.8, 123.0, 126.2, 129.1, 130.4,130.5, 132.1, 132.2, 133.1, 133.3, 134.6, 134.7, 135.1, 135.4, 137.5,137.7, 138.1, 138.2, 139.3, 139.4, 139.5, 139.7, 140.0, 140.1, 153.8.

2e. Synthesis of Further Exemplary Compounds

The synthesis of exemplary compounds according to formula I can beachieved under the reaction conditions as described above (Chapter 2a to2d).

N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A5-9:R=OMe, Cy=3-thienyl)

Synthesis works according to the preparation of A4-1 or A4-4 when usingN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and 3-thienylacetic acid (A3-9: Cy=3-thienyl) (purchasable from Sigma-Aldrich, Munich(Germany); order number: 220639) and subsequent reaction according tothe synthesis of A5-1.

N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A7-9:Cy=3-thienyl)

Synthesis works according to the preparation of A7-1 when usingN-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A5-9:R=OMe, Cy=3-thienyl).

N-(2-Benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-10: R=OMe, Cy=2-benzo[b]thienyl)

Synthesis works according to the preparation of A4-1 or A4-4 when usingN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and2-benzo[b]thienyl acetic acid (A3-10: R=OMe, Cy=2-benzo[b]thienyl)(purchasable from Rare Chemicals, Kiel (Germany); order number: GT HW0344) and subsequent reaction according to the synthesis of A5-1.

N-(2-Benzo[b]thienylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine(A7-10: Cy=2-benzo[b]thienyl)

Synthesis works according to the preparation of A7-1 when usingN-(2-benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-10: R=OMe, Cy=2-benzo[b]thienyl).

N-(3-Benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-11: R=OMe, Cy=3-benzo[b]thienyl)

Synthesis works according to the preparation of A4-1 or A4-4 when usingN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and3-benzo[b]thienyl acetic acid (A3-11: R=OMe, Cy=3-benzo[b]thienyl)(purchasable from Alfa Aesar, Karlsruhe (Germany); order number: LO 5855or Maybridge, Tintagel, Cornwall (UK); order number: S11080) andsubsequent reaction according to the synthesis of A5-1.

N-(3-Benzo[b]thienylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine(A7-11: Cy=3-benzo[b]thienyl)

Synthesis works according to the preparation of A7-1 when usingN-(3-benzo[b]thienylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine(A5-11: R=OMe, Cy=3-benzo[b]thienyl).

N-(8-Methoxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine(A5-12: R=OMe, Cy=2-pyrazolo[1,5-a]pyridinyl)

Synthesis works according to the preparation of A4-1 or A4-4 when usingN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and2-pyrazolo[1,5-a]pyridinyl acetic acid (A3-12: R=OMe,Cy=2-pyrazolo[1,5-a]pyridinyl) (synthesis according to literature:Awano, K. Chem Pharm Bull 1992, Vol 40, p 631; Lober, S Bioorg Med ChemLett 2002, Vol 12, p 2377) and subsequent reaction according to thesynthesis of A5-1.

N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine(A7-12: Cy=2-pyrazolo[1,5-a]pyridinyl)

Synthesis works according to the preparation of A7-1 when usingN-(8-methoxytetralin-2-yl)-N-propyl-N-(2-pyrazolo[1,5-a]pyridinylethyl)amine(A5-12: R=OMe, Cy=2-pyrazolo[1,5-a]pyridinyl).

N-(8-Methoxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine(A5-13: R=OMe, Cy=3-pyrazolo[1,5-a]pyridinyl)

Synthesis works according to the preparation of A4-1 or A4-4 when usingN-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R=OMe) and3-pyrazolo[1,5-a]pyridinyl acetic acid (A3-13: R=OMe,Cy=3-pyrazolo[1,5-a]pyridinyl) (synthesis according to literature:Gmeiner, P. Arch Pharm 1988, Vol 321, p 517) and subsequent reactionaccording to the synthesis of A5-1.

N-(8-Hydroxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine(A7-13: Cy=3-pyrazolo[1,5-a]pyridinyl)

Synthesis works according to the preparation of A7-1 when usingN-(8-methoxytetralin-2-yl)-N-propyl-N-(3-pyrazolo[1,5-a]pyridinylethyl)amine(A5-13: R=OMe, Cy=3-pyrazolo[1,5-a]pyridinyl).

Exemplary compounds according to formula I with R=OR1 and withR1=—C(═O)R2 can be synthesized via reaction of compounds according toformula A7 with appropriate acid derivatives according to formula 8under the conditions which are common to form an ester bound to getcompounds according to formula 8

-   -   and wherein in anyone of the formulas A7, A8 and A9 the residues        R2 and Cy are as defined further above and in the disclosures        for compounds of formula I and    -   wherein W is selected of chloro, bromo or alkylcarbonyloxy.

Acetic acid 7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester(A9-1: R2=Me, Cy=2-thienyl)

The synthesis of the ester A9-1 works when reactingN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A7-1:Cy=2-thienyl) with acetic acid chloride (A8-1: W=Cl, R2=Me) according tostandard conditions to form ester groups for example in pyridine at roomtemperature for several hours.

Carbonic acid ethyl7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester(A9-2:R2=ethyloxy, Cy=2-thienyl)

The synthesis of the ester A9-2 works when reactingN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A7-1:Cy=2-thienyl) with ethoxycarbonyl chloride (A8-2: W=Cl, R2=ethyloxy)according to standard conditions to form ester groups for example inpyridine at room temperature for several hours.

To synthesize compounds according to formula I with R is equal to ahydroxy substituted (C1-C6)alkylcarbonyloxy group specified by formulaA11 (n=1,2,3) the appropriate acid derivative may be introduced byutilizing cyclic anhydric acids of different ring seizure according toformula A10 (n=1,2,3) to get the □-substituted carboxy derivatives whichcan be reduced by complex hydrides like borane (BH₃) to achievecompounds according to formula A11 with n=1, 2 or 3 and with Cy beingdefined as described further above and in the disclosures for compoundsof formula I

4-Hydroxybutanoic acid7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester (A11-1: n=1)

Reaction ofN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A7-1:Cy=2-thienyl) with succinic acid anhydride (A10-1: n=1) according tostandard acylation conditions for example in pyridine at roomtemperature for several hours yields the appropriate succinic acid monoester which can be reduced by BH₃ to get the 4-hydroxybutanoic acidester A11-1 (n=2).

5-Hydroxypentanoic acid7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl ester (A11-2: n=2)

Reaction ofN-(8-hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine (A7-1:Cy=2-thienyl) with glutaric anhydride (A10-2: n=2) according to standardacylation conditions for example in pyridine at room temperature forseveral hours yields the appropriate glutaric acid mono ester which canbe reduced by BH₃ to get the 5-hydroxypentanoic acid ester A11-2 (n=2).

The synthesis of compounds according to formula I with R is equal toS(C1-C3)alkyl specified by formula A12 can be achieved when startingwith halogen substituted precursors according to formula A1 (R=Hal)which are derivatized as described above to get compounds according toformula I (R=Hal). Halogen metal exchange utilizing n-butyl lithium andfinal substitution of the metal atom with alkyl sulfids yield inalkylthio substituted compounds according to formula 12

N-(8-Methylthiotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine(A12-1: (C1-C3)alkyl=Me, Cy=2-thienyl)

The precursor 8-bromo-2-tetralone (A1-2: R=Br) (available according toEP0385658) can be reacted as described for A2-1, A4-1 or A4-4 and A5-1to get N-(8-bromotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amineaccording to formula I (R=Br, Cy=2-thienyl). Halogen metal exchange inTHF using n-butyl lithium results in the 8-lithiated derivative which isreacted with dimethyldisulfide to yield A12-1.

The preparation of compounds bearing a nitrogene in position 8 of thetetraline scaffold according to formula I (R=di(C1-C3)alkylamino orNHR3) starts from the precursor 8-nitro-2-tetralone (A1-3). Reductiveamination as described for A2-1 and subsequent amidation using acidderivatives according to formula 3 lead to amids as displayed in formulaA4-7. Reduction of the amide group with complex hydrids like lithiumaluminium hydride results in the formation of the tertiary amine and thereduction of the nitro to the amino group in position 8 of the compoundsaccording to formula 13.

N-(8-Aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A13-1:R′=R″=H, Cy=2-thienyl)

Synthesis works according to the preparation of A2-1 starting from8-nitro-2-tetralone (A1-3) (purchasable from Anichem, North Brunswick,N.J.; order number: N10122 or from Accel Pharmtech, East Brunswick,N.J.; order number: C1061). Amidation according to the preparation ofA4-1 or A4-4 gives the intermediate A4-7 (Cy=2-thienyl) with can bereduced with LiAlH₄ in diethyl ether to getN-(8-aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A13-1:R′=R″=H, Cy=2-thienyl).

N-(8-Methylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine(A13-2: R′=Me, R″=H, Cy=2-thienyl)

Reductive amination ofN-(8-aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A13-1:R′=R″=H, Cy=2-thienyl) with stoichiometrically equal amounts ofpropylamine in the presence of NaBH₃CN or NaBH(OAc)₃ gives themonomethylamineN-(8-methylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine(A13-2: R′=Me, R″=H, Cy=2-thienyl).

N-(8-Dimethylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine(A13-3: R′=R″=Me, Cy=2-thienyl)

Reductive amination ofN-(8-aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A13-1:R′=R″=H, Cy=2-thienyl) with an excess of propylamine and NaBH₃CN orNaBH(OAc)₃ gives the dimethylamine derivativeN-(8-dimethylaminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine(A13-3: R′=R″=Me, Cy=2-thienyl).

7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl formamide (A13-4:R′=formyl, R″=H, Cy=2-thienyl)

Aminolysis of the primary amineN-(8-aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A13-1:R′=R″=H, Cy=2-thienyl) with formic acid ethyl ester under the commonconditions of an amide formation achieves7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl formamide (A13-4:R′=formyl, R″=H, Cy=2-thienyl).

7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-yl carbamic acidethyl ester (A13-5: R′=ethyloxycarbonyl, R″=H, Cy=2-thienyl)

Aminolysis of the primary amineN-(8-aminotetralin-2-yl)-N-propyl-N-[2-(3-thienyl)ethyl]amine (A13-1:R′=R″=H, Cy=2-thienyl) with ethoxycarbonyl chloride in the presence ofpyridine gives 7-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin-1-ylcarbamic acid ethyl ester (A13-5: R′=ethyloxycarbonyl, R″=H,Cy=2-thienyl).

B. Biological Experiments

1) Receptor Binding Assays

Receptor binding data were determined when performing competitionbinding assays with membrane preparations of cloned cells (stablytransfected Chinese Hamster Ovary cells (CHO)) expressing the humanreceptors and the following radioligands: [³H]spiperone at the humandopamine receptor subtypes hD2_(long), hD2_(short), D3, and hD4.4.Furthermore, membrane homogenates prepared from porcine striatal orcortical tissue were established together with specific radioligands toinvestigate the following receptors: [³H]SCH 23390 at the porcinestriatal pD1 dopamine receptor, [³H]WAY100635 at the porcine corticalp5-HT1a and [³H]ketanserin at the porcine cortical p5-HT2 serotoninreceptor as well as [³H]prazosin at the porcine cortical pal and[³H]RX821002 at the porcine cortical pα2 adrenergic receptor (Huebner, HJ Med Chem 2000, Vol 43, p. 756, Schlotter, K J Med Chem 2005, Vol 48,p. 3696).

The results are displayed in Table 1.

Selectivity ratios were calculated by division of the K_(i) values ofthe various compounds at the respective receptors through the K_(i)values at the 5HT1a receptor. Results are displayed in Table 2.

Compounds of formula I and II disclosed herein, specifically thosewherein Cy is a 5 or 6 membered aromatic or heteroaromatic ring, forexample those which are selected from the group of phenyl, thienyl,furanyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl,pyridyl, pyrimidyl, which ring maybe unsubstituted or substituted withone or two groups R4, as further defined herein, show excellent affinityto the 5-HT1a receptor and remarkable selectivity over dopaminergic andadrenergic receptors. A particular high selectivity is displayed bythose compounds wherein R is a polar group such as e.g. hydroxyl, and/orif Cy is thienyl or phenyl. Table 2a shows a comparison of the compoundsof formula II with a free hydroxyl group with the comparative compound8-OH-DPAT.

Those compounds of the present invention wherein Cy is a bicyclic ringsystem Y or adamantyl tend to have a better binding to dopaminergic D2,D3 and/or D4 receptors being expressed in lower nanomolar K, values andmay in some instances serve as combined dopamine/serotonin receptoragonist (see Table 2b).

In addition, representative compounds have been shown to be fullagonists at the 5-HT1a receptor with EC₅₀ values in the low nanomolarrange (see Table 3 and Chapter b) Functional assays).

TABLE 1 Receptor binding data of the compounds 1-14 and the reference8-OH-DPAT at the dopamine, serotonin and adrenergic receptors (K_(i)values in [nM] asmeans of 2-8 individual experiments each done astriplicate) compound p5-HT1a p5-HT2 pD1 hD2_(long) hD2_(short) hD3 hD4.4pα1 pα2 1 0.73 3 600 9 400 260 260 190 190 170 68 2 2.9 12 000  6 700160 390 57 390 200 n.d.  1a 0.52 2 500 8 800 240 260 100 100 640 56  2a7.3 6 000 5 200 750 840 230 880 140 64  1b 1.8 5 500 5 400 520 290 49690 200 n.d.  2b 6.7 3 900 3 300 85 58 32 760 140 n.d. 3 0.62 5 800 9100 760 170 190 590 140 n.d. 4 2.5 4 200 7 300 330 230 51 530 190 60 51.1 6 600 6 200 340 86 95 570  87 n.d. 6 5.5 4 900 9 500 340 260 110 470230 n.d. 7 1.7 1 700 2 400 140 90 130 490  78 n.d. 8 24 4 400 6 200 300180 110 940 510 n.d. 9 3.5 1 600 2 600 16 12 39 350 570 n.d. 10  65 14000  12 000  380 190 260 1 800  4 900  n.d. 11  0.32  930  3100 34 16 52  7.4 170 n.d. 12  1.8 2 200  2600 38 17 11   3.5  92 n.d. 13  15 2 1003 500 990 640 170  87 930 n.d. 14  50 7 300 1 900 48 35 33 110 280 n.d.R-(+)-8- 1.2 2 100 3 300 140 100 43 210 250 n.d. OH-DPAT (n.d. = notdetermined)

TABLE 2 Receptor binding and selectivity data for compounds 1-14 and thereference 8- OH-DPAT: 5-HT1a receptor vs dopamine, 5-HT2 serotonin and□1 adrenergic receptors; for each compound K_(i) values [nm] (upper row)and selectivity ratios derived from the equation (ratio = K_(i) forp5-HT1a/K_(i) for the respective receptor) (lower row) are listed Table2a: Selective 5-HT1a agonists p5- Selec- compound HT1a tivity pD1hD2_(long) hD2_(short) hD3 hD4.4 p5-HT2 pα1 R-(+)-8- 1.2 K_(i) [nM] 3300 140 100 43 210 2 100 250 OH-DPAT 1 ratio 2 800 120 83 36 180 1 800210 1 0.73 K_(i) [nM] 9 400 260 260 190 190 3 600 170 1 ratio 13 000 360 360 260 260 4 900 230  1a 0.52 K_(i) [nM] 8 800 240 260 100 100 2500 640 1 ratio 17 000  460 500 190 190 4 800 1 200   1b 1.8 K_(i) [nM]5 400 520 290 49 690 5 500 200 1 ratio 3 000 290 160 26 380 3 100 110 30.62 K_(i) [nM] 9 100 760 170 190 590 5 800 140 1 ratio 15 000  1 200 270 310 950 9 400 230 5 1.1 K_(i) [nM] 6 200 340 86 95 570 6 600  87 1ratio 5 600 310 80 86 520 6 000  79 7 1.7 K_(i) [nM] 2 400 140 90 130490 1 700  78 1 ratio 1 400  82 53 76 290 1 000  46

TABLE 2b Mixed D2/D3/5-HT1a agonists p5- Selec- compound HT1a tivity pD1hD2_(long) hD2_(short) hD3 hD4.4 p5-HT2 pα1 9 3.5 K_(i) [nM] 2 600 16 1239 350 1 600 570 1 ratio  740 4.6 3.4 11 100  1600 160 10 65 K_(i) [nM]12 000  380 190 260 1 800  14 000  4 900  1 ratio  180 5.8 2.9 4.0  28 220  75 13 15 K_(i) [nM] 3 500 990 640 170  87 2 100 930 1 ratio  23066 43 11   5.8  140  62 14 50 K_(i) [nM] 1 900 48 35 33 110 7 300 280 1ratio   38 0.96 0.70 0.66   2.2  150   5.62) Functional Assays

The 5-HT1a receptor activation was determined in a [³⁵S]GTP□S assay asdescribed in literature (Schlotter, K J Med Chem 2005, Vol 48, p 3696).This assay is based on the determination of the binding of theradioactive ligand [³⁵S]GTP□S to membranes carrying the proteins forsignal transduction of GPCRs. Specific binding of [³⁵S]GTP□S isstimulated by activation of the stably expressed human 5-HT1a receptorin a dose-dependent way by agonists for this GPCR and is determined bymeasuring the radioactive label of the membrane. Non-linear regressionanalysis of the resulting dose-response curves yields the EC₅₀ value in[nM] representing the half maximal concentration which is necessary toactivate the receptor completely. Furthermore, the maximal intrinsicactivity of the tested compound in [%] can be derived relative to theeffect of the reference compound serotonin.

The results of the functional tests of representative compounds of thisdisclosure are listed in Table 3. Representative curves for thecompounds 1 and 2 relative to the reference serotonin (5-HT) aredisplayed in FIG. 1.

Compound 1 and its (R)-enantiomer 1a show full agonist activity at thehuman 5-HT1a receptor with a [³⁵S]GTP□S incorporation of 103% relativeto the effect of serotonin (=100%) and with EC₅₀ values of 0.65-1.9 nMbeing very similar to the K_(i) values determined in the radioliganddisplacement experiments for receptor binding. Similar effects weremeasured for the 8-methoxy derivatives 2 and 2a and the adamantylsubstituted compound 9.

TABLE 3 Functional activity at the 5-HT1a receptor determined in a[³⁵S]GTP□S assay (mean values of 2-8 individual experiments) intrinsicactivity compound EC₅₀ [nM] [% rel. to serotonin] serotonin 3.6 100 11.9 103 1a 0.65 103 2 6.3 91 2a 1.1 82 9 1.9 883) Animal Pain Test (Formalin Assay)

The formalin assay is a chemically induced tonic pain model whichindicates a compound's ability to treat pain. The formalin test is beingwidely accepted as a valid basic model of persistent clinical pain, andmay indicate a compound's efficacy in neuropathic and/or inflammatorypain conditions.

Compound 1 and a comparator (gabapentin 100 mg/kg) were administered togroups of 5 or 10 CD-1 (Cr1.) derived male mice weighing 24±2 g. Testsubstances and vehicle (0.2% HPMC/0.9% NaCl) were each administered byintraperitoneal injection (gabapentin) or oral gavage (compound 1) 15 or30 minutes before subplantar injection of formalin (0.02 ml, 2%solution). Reduction of the formalin-induced hind paw licking timerecorded at 5-minute interval during the following 0-to 35-minute afterformalin injection by 50 percent or more (≧50%) indicated significantanalgesic activity. Also, statistical analysis was performed by usingone-way ANOVA followed by Dunnett's test to compare the testcompound-treated and vehicle control groups. Significance is consideredat P<0.05 level. Acute toxic symptoms and autonomic effects wereobserved after the administration of test compounds.

Compound 1 showed significant analgesic effect at the 10-20 minutesperiod after 10 mg/kg oral administration (FIG. 2 and Table 4). Whilethe 3 mg/kg showed some effect, no analgesic effect has been observedafter 1 mg/kg administration. Hence, compound 1 dose-dependentlydemonstrated analgesic effect after oral administration (Table 4).

TABLE 4 Results of the formalin assay after oral administration ofcompound 1 vs vehicle Hind Paw Licking Times in Seconds (% Inhibition)observation interval (minutes) 0-5 5-10 10-15 15-20 20-25 25-30 30-35vehicle 76.9 ± 7.9 2.6 ± 1.5 54.5 ± 15  100.8 ± 18.6 62.4 ± 17.1 9.6 ±4.1  14.2 ± 13.3 5 ml/kg compound 1 63.4 ± 7.2 10.2 ± 3.9  25.1 ± 11.656.7 ± 18  54.7 ± 9.4  54.7 ± 15.1 24.7 ± 9.8 5 mg/kg (18%)  (0%) (54%)(44%) (12%) (0%)  (0%) compound 1 64.3 ± 7.3 0 ± 0 2.0* ± 1.8  31.6* ±12.3 37.5 ± 13.6 29.9 ± 12.7 12.8 ± 8.8 10 mg/kg (16%) (100%) (96%)(69%) (40%) (0%) (10%)4) Penetration Through Skin

The in vitro permeation of compound 1 through pig skin from saturatedsolution (f1) and from a patch (f2) was investigated.

4.1) Pig Skin Permeation from Saturated Solution

For the permeation experiments horizontal cells with an acceptor anddonor volume of approx. 23 mL of phosphate buffer pH 6.2 were used. Thedonor cells contained saturated solutions of compound 1 (2 mg/mL) inphosphate buffer pH 6.2. The experiments were performed at a temperatureof 32° C. and the acceptor and donor media were slowly stirred. For thestudy pig leg skin with thickness of 300-500 μm were used. Theexperiments were performed in triplicate (n=3) over a period of 48hours. During this time period six samples at different time points(after 2, 4, 6, 8, 24 and 48 hours) were taken. After each individualincubation period the concentration of the test compound in the acceptormedium was analysed by HPLC at 275 nm, 20° C., flow rate 2.0 mL/min inacetonitrile/water/TFA.

Evaluation: The concentration of the test compound in the acceptormedium was calculated by using an external standard solution with knownconcentration. Then the concentration of test compound was correlatedwith the incubation time by linear regression. The flux rate [μg/cm²/h]is equivalent to the slope of the linear equation.

Results: The average flux rate of Compound 1 from saturated solution wasdetermined to be 4.0 μg/cm²/h (mean value of cells 1-3).

4.2) Pig Skin Permeation from Patch

For this permeation experiments Franz diffusion cells with a diffusionarea of 2.54 cm² and an acceptor volume of approx. 100 mL were used. Forthe study pig leg skin with a thickness of 300-500 μm was used. Thepermeation experiments were performed at a temperature of 32° C. and theacceptor medium (phosphate buffer pH 6.2) was slowly stirred. A patch of2.54 cm² area comprising about 5 wt % of compound 1 in a hydrophobicadhesive layer was fixed on the skin surface. The experiments wereperformed in triplicate (n=3) over a period of 48 hours. During thistime period six samples at different time points (after 2, 4, 6, 8, 24and 48 hours) were taken. After each individual incubation period theconcentration of the test compound in the acceptor medium was analysedby HPLC at 275 nm, 20° C., 2.0 mL/min in acetonitrile/water/TFA.

Results: The average flux rate of Compound 1 from patch was 4.0μg/cm²/h.

The results of the pig skin permeation experiments are summarized inTable 5.

TABLE 5 Pig skin permeation experiments with compound 1 Patch Flux RateMeasured Flux Rate per cm²/h 4.0 μg Extrapolated daily flux rate per 20cm² patch/24 hrs 1.92 mg per 30 cm² patch/24 hrs 2.88 mg

The flux rate through isolated pig skin both from saturated solution aswell as from a drug-in-adhesive patch was identically. The achieved fluxrate with a non-optimized patch is already deemed sufficient to delivera therapeutically effective amount through the skin (e.g. anextrapolated delivery of about 2 mg/24 hrs for a 20 cm² patch). Furtherimprovement of the flux rate may be possible by optimization of thepatch formulation.

5) Movement Disorder Tests

The movement disorder experiments were designed to measure and observethe ability of aminotetraline derivatives to counteract L-DOPA-inducedAbnormal Involuntary Movement (AIMs). The selected test compound, A2M13677, is a racemic mixture of the amino tetraline derivative,N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,referred to on p.10 of this application as compound 1, however, any ofthe amino tetraline derivatives described above may be substituted tocounteract involuntary movements including L-DOPA induced involuntarymovement, including those compounds which follow the general formuladescribed in this application on p. 4, lines 10-15 and p. 10-11. In thisexample, the amino tetraline derivative substituted R=H andCy=2-thienyl.

The unilateral 6-OHDA lesion will be recognized by those in the art as aclassical animal model for the assessment of movement disorder drugssuch as anti Parkinson Drugs. For example, L-DOPA may be used forclinical treatment of Parkinson's Disease but may induce circlingbehaviour in this model, indicating the stimulation of hypersensitivedopamine receptors in the lesioned brain region that is reminiscent ofParkinson's Disease degeneration of dopaminergic neurones. While L-DOPAmay greatly improve the classical symptoms of Parkinson's Disease,L-DOPA, when given chronically induces abnormal involuntary movements(dyskinesias). These L-DOPA induced dyskinesias are observed in themajority of long-term Parkinson's Disease patients and can become themost prominent symptom. 6-OHDA lesion rats chronically treated withL-DOPA develop abnormal involuntary movement that are comparable tothose observed in patients. Consequently, this animal model is used forthe evaluation of novel anti-dyskinetic drugs. Therefore, drug-naiveunilateral 6-OHDA lesioned rats were chronically treated, once a day,with saline (n=8) or a mixed solution made of 15 mg/kg of L-DOPA and 5mg/kg of benserazide administered subcutaneously (sc) (n=16) over aperiod of two weeks in order to induce stable abnormal involuntarymovement levels (in the latter group).

The testing phase consisted of two days referred to as the“pre-test/post-test” comparison, as seen in both FIGS. 4( a) and 4(b).At the “pre-test”, the 8 rats from the “saline” condition group receivedthe vehicle injection via intraperitoneal injection (ip) 5 minutes afterthe saline injection (sc). The 16 rats from the “L-DOPA” condition groupreceived the vehicle injection (ip) 5 minutes after theL-DOPA/benserazide administration (sc). The objective of the “pretest”was to assess the basal level of abnormal involuntary movements,resulting from the chronic treatment with L-DOPA/benserazide.

During the “post-test”, the 8 rats from the “saline” condition groupreceived A2M 13677 (ip) 5 minutes after the saline administration (sc),while the 16 rats from the “L-DOPA” condition group received A2M 13677(ip) 5 minutes after the L-DOPA/benserazide administration (sc).

For both pre- and post-tests, the rats were placed into their respectivetesting cages and an observer began counting the number rotationsimmediately after the second injection (either the vehicle and/or A2M13677), overall, at 10 min after the first injection (saline or L-DOPA).

Abnormal involuntary movements were scored using a multi-subjecttime-sampling technique. Video recordings started at 20 minutes afterthe L-DOPA/benserazide injection and continually recorded over a periodof 70 minutes. Six video samples of one minute each were collected andtransferred definitively on CDs. The first video sample was collected at10 minutes after the beginning of the video recording and the followingat 20, 30, 40, 60 and 80 minutes.

These samples lasted for 1 minute, wherein during each sample, 50 secswere scored by one trained observer, who was blind to the dose treatmentgroup and test.

Three behavioral categories were defined to classify each rat's abnormalinvoluntary movements expressed under L-DOPA/benserazide. Thesebehavioral categories included grabbing, axial posture and dystonia.During each of the six, 50-sec video samples, which included a totalscored observation time of 300 sec, the time (in sec) spent on each ofthese behavioral categories was recorded.

These behavioral categories, were defined according to the rat bodyposition and the number of paws in contact with the floor as follows:

-   -   1) Grabbing: horizontal body position, grabbing-like movements        of the forelimb contralateral to the lesion (flexion-extension,        abduction-adduction and circumduction), accompanied by        contralateral rotations on three paws.    -   2) Axial posture: vertical body position; lateral deviation of        the head, neck and trunk towards the side contralateral to the        lesion (the angle between the head and the nose<180°); often        accompanied with grabbing and contralateral rotations performed        on the hindlimbs.    -   3) Dystonia: vertical body position, sustained and severe body        torsion (angle between the head and the nose>180°) towards the        side contralateral to the lesion; may include choreiform        twisting movements; often accompanied by rotations on hindlimbs.

Grabbing, axial and dystonia were considered as L-DOPA-induced abnormalinvoluntary movements. We considered the following ascending order ofseverity: grabbing<axial<dystonia. To facilitate the comprehension ofthe results these three different types of behaviors representingabnormal involuntary movements were summed in order to get a generalabnormal involuntary movement score.

The presence and intensity of the L-DOPA-induced abnormal involuntarymovements were analyzed using non-parametric statistics (because ofabsence of normality and cut-off at 300 sec). Data from “pre-/post-test”comparisons were analyzed using Wilcoxon matched pairs test, separatelyfor each behavioral category and dose. The Wilcoxon matched pairs testswere performed separately for each time-sample at 10, 20, 30, 40, 60 and80 minutes after the beginning of the video recordings.

L-DOPA/benserazide treated rats displayed very high levels of abnormalinvoluntary movements, during the “pretest” session as shown in FIGS. 4(a) and 4(b). Those levels of abnormal involuntary movements nearlyreached the maximum of the time available (second) for behavioralquantification (i.e. 50 seconds). During the post-test session, abnormalinvoluntary movements were marked reduced by treatment with A2M 13677 atboth the doses of 1 mg/kg depicted in FIG. 4( a) and at 3 mg/kg depictedin FIG. 4( b).

The data of the involuntary movement test is represented in FIGS. 4( a)and 4(b) which depict the pre-test and post test results. The datarepresents the mean+/−SEM of “uncontaminated circling”, expressed by 8Sprague-Dawley rats per group. At the pretest, rats received oneinjection (sc) of L-DOPA (15 mg/kg) I benserazide (5 mg/kg), (sc) and 5minutes later, one injection (ip) of vehicle. At the post-test, the samerats received one injection (sc) of L-DOPA (15 mg/kg) I benserazide (5mg/kg) (sc) and A2M 13677, 5 min later, at 1 mg/kg in FIG. 4( a) and at3 mg/kg in FIG. 4( b).

A2M 13677, at 1 and 3 mg/kg, significantly decreased the levels ofL-DOPA-induced abnormal involuntary movements in 6-OHDA-lesioned ratschronically treated and primed with an active dose of L-DOPA andbenserazide. Time course analysis of the effects of A2M 13677 onrotational activity showed that A2M 13677 significantly reduced both thelevels of L-DOPA-induced contralateral rotations and the levels ofL-DOPA-induced abnormal involuntary movements. Instead of exhibitingabnormal involuntary movements, other behaviors, like explorativesniffing and grooming, were observed. This shift from rotation toexploration is indicative of transient restoration of the L-DOPAefficacy on motor activity, without behavioral disturbances which maycontaminate the motor movements, rather than an abrupt loss of theanti-Parkinsonian effects of L-DOPA.

C. Physicochemical Characterisation of Compound 1:

1) Stability of Compound 1 in PBS Buffer pH 7.4 and SGF with 0.5% DMSO

5 μL DMSO stock solution of compound 1 (2 mg/mL) were diluted with 955μL PBS buffer pH 7.4 and 995 μL Simulated Gastric Fluid (SGF). Afterdilution the samples were immediately analysed by HPLC. After theinitial injection, each sample solution was repeatedly injected over aperiod of approximately 12 hours.

Results: No degradation of compound 1 in PBS buffer pH 7.4 and simulatedgastric fluid (pH 1-2) over 12 hours at 37° C. was observed.

2) Melting Point

The melting point of compound 1 was determined by DSC. The measurementswere performed in perforated pans with a heating rate of 1° C./min. Themelting point (Tonset) of compound 1 is about 97.5° C.

3) XRPD Measurements

Crystallinity of the free base of compound 1 was confirmed by X-raydiffractogram using Cu k-alpha radiation (lambda=1.540 Å). The maindegrees 2 theta peaks (≧5% relative intensity) are depicted in Table 6and are illustrated in FIG. 3.

TABLE 6 XRPD peaks in degree 2 theta positions (relative intensity in %in brackets) XRPD rel. intensity XRPD rel. intensity XRPD rel. intensitypeaks [%] peaks [%] peaks [%] 6.5605 37.43 11.3713 8.60 13.1904 4.9813.2735 6.72 13.6157 6.37 15.1796 24.11 15.2668 79.16 16.3749 46.5815.5371 9.31 16.6824 100.00 17.3662 28.74 18.5872 19.80 19.8581 13.2820.5278 16.25 20.6209 17.00 21.1673 10.72 21.4459 63.22 23.5955 58.4423.9294 23.04 24.7873 16.07 25.1693 20.63 25.5412 8.14 26.2780 5.6126.5836 18.85 27.9429 6.90 30.3043 5.34 36.4145 8.13

What is claimed is:
 1. A method for treating a movement disordercomprising the steps of: administering to a recipient, a compound offormula I

wherein R is OR1, di(C1-C3)alkylamino, SH, S(C1-C3)alkyl or NHR3; R1 ishydrogen, a group —C(═O)R2, —SO₂CF₃, or (C1-C3)alkyl which isunsubstituted or substituted with one or more halogen atoms; R2 is(C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl orphenyl(C1-C3)alkyloxy, wherein the phenyl group is optionallysubstituted with one or more substituents selected from (C1-C3)alkoxy,(C1-C3)alkyl, halogen, or CF_(3;) R3 is hydrogen, (C1-C3)alkyl, formyl,(C1-C3)alkylcarbonyl, (C1-C3)alkoxycarbonyl, or (C1-C3)alkylaminocarbonyl; Cy is an aromatic, heteroaromatic or non-aromatic cyclic groupX, Y or Z, wherein X is a 5 membered aromatic or heteroaromatic ringwhich is unsubstituted or substituted with one or two groups R4, or a 6membered aromatic or heteroaromatic ring which is substituted with oneor two groups R4; Y is a bicyclic aromatic or heteroaromatic ring systemwhich is unsubstituted or substituted with one to three groups R5 andwhich ring system is selected from among

wherein the bond crossed by a dotted line indicates the attachment siteof the group Y to the aminotetraline scaffold; wherein each R4 and R5 isindependently selected from halogen, hydroxyl, CF₃, (C1-C3)alkyl, or(C1-C3)alkoxy, wherein each alkyl or alkoxy may be substituted with oneor more halogens or a hydroxyl group; and Z is adamantyl which isunsubstituted or substituted with methyl and/or hydroxyl, including itsenantiomers and pharmaceutically acceptable salts.
 2. The method ofclaim 1, wherein the movement disorder is an L-DOPA associateddyskinesia.
 3. The method of claim 1 wherein R of the compound offormula I is OR1, wherein R1 is methyl, hydrogen or a group —C(═O)R2,wherein R2 is (C1-C6)alkyl or (C1-C6)alkyloxy.
 4. The method of claim 1wherein Cy of the compound of formula I is a 5 or 6 membered aromatic orheteroaromatic ring which is selected from the group of phenyl, thienyl,furanyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl,pyridyl, pyrimidyl, and unsubstituted or substituted with one or twogroups R4.
 5. The method according to claim 1 wherein the compound offormula I administered to a recipient is selected fromN-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,(R)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,(S)-N-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,(R)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,(S)-N-(8-Methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine,N-[2-(4-Hydroxyphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine,N-[2-(4-Methoxyphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine,N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine,N-[2-(2,5-Dimethylphenyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine,N-[2-(1-Adamantyl)ethyl]-N-(8-hydroxytetralin-2-yl)-N-propylamine,N-[2-(1-Adamantyl)ethyl]-N-(8-methoxytetralin-2-yl)-N-propylamine,N-(2-Ferrocenylethyl)-N-(8-hydroxytetralin-2-yl)-N-propylamine,N-(2-Ferrocenylethyl)-N-(8-methoxytetralin-2-yl)-N-propylamine, andpharmaceutically acceptable salts thereof.
 6. The method of claim 1,wherein the compound of formula I isN-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine or apharmaceutically acceptable salt thereof.
 7. The method of claim 3,wherein R2 is (C1-C6)alkyl.
 8. A method of treating a movement disordercomprising the steps of: administering to a recipient, a compound offormula II

wherein R1 is hydrogen, a group —C(═O)R2, or (C1-C3)alkyl which isunsubstituted or substituted with one or more halogen atoms, R2 is(C1-C6)alkyl, (C1-C6)alkyloxy, phenyl, phenyl(C1-C3)alkyl orphenyl(C1-C3)alkyloxy, wherein the phenyl group is optionallysubstituted with one or more substituents selected from (C1-C3)alkoxy,(C1-C3)alkyl, halogen or CF₃; wherein Cy is a 5 membered aromatic orheteroaromatic ring selected from the group of phenyl, thienyl, furanyl,each of which is unsubstituted or substituted with one or two groups R4,or a 6 membered aromatic or heteroaromatic ring selected from the groupof phenyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyrazolyl,pyridyl, pyrimidyl, which is substituted with one or two groups R4,wherein each R4 is independently selected from halogen, (C1-C3)alkyl, or(C1-C3)alkoxy, wherein each alkyl or alkoxy may be substituted with oneor more halogens or a hydroxyl group, including its enantiomers andpharmaceutically acceptable salts.
 9. The method of claim 8 wherein R1is hydrogen, methyl, or a group —C(═O)R2, wherein R2 is (C1-C6)alkyl or(C1-C6)alkyloxy; and Cy is thienyl which is unsubstituted or substitutedwith one or two groups R4, which are selected from halogen, hydroxyl,(C1-C3)alkyl, or (C1-C3)alkoxy, wherein each alkyl or alkoxy may besubstituted with one or more halogen atoms or a hydroxyl group, orphenyl, which is substituted with one or two groups R4, which areselected from halogen, hydroxyl, (C1-C3)alkyl, or (C1-C3)alkoxy, whereineach alkyl or alkoxy can be substituted with one or more halogen atomsor a hydroxyl group.
 10. The method according to claim 8, wherein R1 ishydrogen or methyl and Cy is phenyl or thienyl, wherein the phenyl isoptionally substituted with one or two groups R4 which are independentlyselected from hydrogen, hydroxyl, (C1-C3)alkyl, (C1-C3)alkoxy, or CF₃.11. The method according to claim 9, wherein R2 is (C1-C3)alkyl.
 12. Themethod according to claim 1, wherein the compound of formula I isN-(8-Hydroxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine or apharmaceutically acceptable salt thereof, which is enantiopure in (R)configuration.
 13. The method according to claim 1, wherein the movementdisorder includes at least one of grabbing, axial posture and dystonia.